TYPE Review

PUBLISHED 06 March 2024

DOI 10.3389/fcimb.2024.1360586

A comprehensive review of
OPEN ACCESS monkeypox virus and
EDITED BY
Mohd Ahmar Rauf,
Wayne State University, United States
mpox characteristics
REVIEWED BY
Ali Tavakoli Pirzaman,
Emmanuel Alakunle 1, Daniel Kolawole 1, Diana Diaz-Cánova 2,
Babol University of Medical Sciences, Iran Faith Alele 3, Oyelola Adegboye 4, Ugo Moens 2*
Sanda Ravlić,
University of Zagreb, Croatia and Malachy Ifeanyi Okeke 1*
*CORRESPONDENCE 1
Department of Natural and Environmental Sciences, American University of Nigeria, Yola, Nigeria,
Ugo Moens 2
Department of Medical Biology, UIT – The Arctic University of Norway, Tromsø, Norway, 3 School of
umo000@post.uit.no Health, University of the Sunshine Coast, Sippy Downs, QLD, Australia, 4 Menzies School of Health
Malachy Ifeanyi Okeke Research, Charles Darwin University, Darwin, NT, Australia
malachy.okeke@aun.edu.ng

RECEIVED 23 December 2023

ACCEPTED 20 February 2024 Monkeypox virus (MPXV) is the etiological agent of monkeypox (mpox), a
PUBLISHED 06 March 2024
zoonotic disease. MPXV is endemic in the forested regions of West and Central
CITATION
Africa, but the virus has recently spread globally, causing outbreaks in multiple
Alakunle E, Kolawole D, Diaz-Cánova D,
Alele F, Adegboye O, Moens U and Okeke MI non-endemic countries. In this paper, we review the characteristics of the virus,
(2024) A comprehensive review of including its ecology, genomics, infection biology, and evolution. We estimate by
monkeypox virus and mpox characteristics.
phylogenomic molecular clock that the B.1 lineage responsible for the 2022
Front. Cell. Infect. Microbiol. 14:1360586.
doi: 10.3389/fcimb.2024.1360586 mpox outbreaks has been in circulation since 2016. We interrogate the host-virus
COPYRIGHT interactions that modulate the virus infection biology, signal transduction,
© 2024 Alakunle, Kolawole, Diaz-Cánova, pathogenesis, and host immune responses. We highlight the changing
Alele, Adegboye, Moens and Okeke. This is an
pathophysiology and epidemiology of MPXV and summarize recent advances
open-access article distributed under the terms
of the Creative Commons Attribution License in the prevention and treatment of mpox. In addition, this review identifies
(CC BY). The use, distribution or reproduction knowledge gaps with respect to the virus and the disease, suggests future
in other forums is permitted, provided the
original author(s) and the copyright owner(s) research directions to address the knowledge gaps, and proposes a One
are credited and that the original publication Health approach as an effective strategy to prevent current and future
in this journal is cited, in accordance with
epidemics of mpox.
accepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these terms.

KEYWORDS

monkeypox, genomics, evolution, antivirals, epidemiology, infection biology, biosafety,

one health

1 Introduction
Monkeypox virus (MPXV) is the etiological agent of a zoonotic disease called monkeypox
(mpox). It is a double-stranded DNA (dsDNA) virus belonging to Orthopoxvirus (OPXV)
genus within the Poxviridae family and Chordopoxvirinae as the subfamily (Alakunle et al.,
2020). Other members of this genus include Variola virus (VARV), Cowpox virus (CPXV),
Vaccinia virus (VACV), Camelpox virus (CMLV), Taterapox virus (TATV) and Ectromelia
virus (ECTV). MPXV is divided into Clade I and Clade II, with Clade II subclassified as Clade
IIa and IIb (Happi et al., 2022). For five decades, MPXV was endemic in West and Central

Frontiers in Cellular and Infection Microbiology 01 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

Africa (Earl et al., 2012), and exportation of the virus to non-endemic re-emergence of the disease started in 2017 with an eleven-year-old
regions was rare (Alakunle and Okeke, 2022). However, the incidence boy as the index case in Bayelsa state (Yinka-Ogunleye et al., 2018). At
(since 2017) of mpox outside endemic regions has increased, and the the end of 2017, Nigeria recorded 88 cases, and during this outbreak,
epidemiological profile of the disease within endemic regions has travel-related cases in non-endemic countries were reported, including
changed (Grothe et al., 2022). This may have led to the MPXV the United Kingdom (UK), the United States of America (USA),
emergence and re-emergence in endemic countries in 2022 (Alakunle Israel, and Singapore, between 2018 and 2021 (Adegboye et al., 2022).
and Okeke, 2022). This paper will cover the current state of The first mpox outbreak in a non-endemic country was reported
knowledge on the characteristics of MPXV and mpox, the infection in 2003 in the USA linked to importation of rodents from Ghana
biology, molecular pathogenesis, and evolution of MPXV as well as (Figure 1) (Anderson et al., 2003; Centre for Disease Control, 2003;
the clinical features, diagnosis, epidemiology, and therapeutic options Croft et al., 2007). By the end of the outbreak, 47 people had been
against mpox. In addition, the review will critically interrogate and infected (10 probable and 37 confirmed cases) (Centre for Disease
evaluate the contributions of viral, host, and anthropogenic factors to Control, 2003; Center for Diseases Control and Prevention (CDC),
the emergence and reemergence of mpox across the globe. 2023). There were no other travel-related cases reported until 2018.
Before 1970, there was no documented report of human MPXV Between 2018 to 2021, 11 travel-related mpox cases were recorded in
infection, although the virus had previously caused infections in the UK, Singapore, Israel, and the USA (Figure 1). Of these, four
monkeys and apes (Arita and Henderson, 1968). Infections in resulted in secondary cases: one healthcare worker in the UK was
monkeys were reported in laboratory/captive animals and were infected by contaminated bedding, an adult and a child from a family
first identified in captive monkeys in Denmark in 1958. The first from the UK had a travel history to Nigeria, and one traveler to Israel
human mpox case emerged in a 9-month-old boy in the Democratic who had visited Nigeria in 2018. Between 2019 and 2021, a total of
Republic of the Congo (DRC) in August 1970 (Ladnyj et al., 1972). seven mpox outbreaks occurred outside Africa in Singapore, the UK
Subsequently, six additional mpox cases were identified between and the USA (Figure 1). All travel related cases originated in Nigeria,
September 1970 and April 1971 in Liberia, Sierra Leone and Nigeria with high-throughput sequencing confirming it as Clade II (Vaughan
(Lourie et al., 1972). Since then, MPXV has been reported in several et al., 2018; Erez et al., 2019; Fang et al., 2020; Hobson et al., 2021;
countries and is endemic in Benin, Cameroon, the Central African Bunge et al., 2022). Between 2017 and October 30, 2022, a total of 830
Republic, the DRC, Gabon, Ivory Coast, Liberia, Nigeria, the cases were recorded in 33 out of 36 states in Nigeria (Nigeria Centre
Republic of the Congo, Sierra Leone, and South Sudan (Bass for Disease Control (NCDC), 2022).
et al., 2013; World Health Organization, 2022a). The current global mpox outbreak started in May 2022
Figure 1 displays the global mpox outbreak timeline. Between (Alakunle et al., 2020; Adegboye et al., 2022) and was declared a
1970 and 2021, the cases have been sporadic and geographically public health emergency of international concern on July 23, 2022
limited within endemic regions (Brown and Leggat, 2016; Titanji et al., (Nuzzo et al., 2022). As of August 02, 2023, there were a total of
2022). Notably, the DRC is the only country that continuously reports 88,600 laboratory-confirmed cases and 152 deaths (case-fatality
yearly cases of mpox with tropical rainforest regions accounting for rate, 0.17%) across 113 countries including 106 countries that
98.7% of all cases pre-2022 (Brown and Leggat, 2016; Durski et al., have not historically reported mpox (Figures 2A-C) (World
2018). In Nigeria, sporadic cases were reported in the 1970s; however, Health Organization, 2022). The Americas recorded the highest

FIGURE 1
Timeline of MPXV emergence and re-emergence in endemic regions and globally. Each event timeline indicates the pre-2022 outbreak in endemic
and non-endemic countries and the 2022 mpox outbreak (Durski et al., 2018; World Health Organization, 2022). Note: Cameroon (CMR), the
Central African Republic (CAR), Cote d’Ivoire (CIV), the Democratic Republic of the Congo (DRC), Gabon (GAB), the United Kingdom (GBR), Liberia
(LBR), Nigeria (NGA), Israel (ISR), Sierra Leone (SLE), Singapore (SGP), the Republic of the Congo (COD), South Sudan (SSD), the United States of
America (USA).

Frontiers in Cellular and Infection Microbiology 02 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

number of cases during the 2022 mpox outbreak, with the USA (n = host reservoir remains elusive. While specific host-cell receptors are
29,513) and Brazil (n = 10,168) accounting for 48.32% of the total responsible for cell tropism, the specificity of MPXV is yet to be
cases (Figure 2C). Other notable affected countries include Spain determined. Factors like the monkeypox inhibitor of complement
(n = 7,408), France (n = 4,110), Colombia (n = 3,880), the UK (n = enzymes (MOPICE) and complement control protein (CCP) can
3,730), Germany (n = 3,673), Peru (n = 3,561), Mexico (n = 3,455), influence the viral cellular and tissue tropism (Hudson et al., 2012).
and Canada (n = 1,459). In Africa, Nigeria has the highest mpox Nonetheless, a wide spectrum of tissue and host tropism is expected,
cases with 634 cases. which may explain the possibility of MPXV establishing animal
reservoirs in non-endemic regions (Kmiec and Kirchhoff, 2022).
Organs such as ovaries, kidneys, heart, brain, pancreas, liver, and
2 Ecology, host range, tissue and lung have been identified as some of the tissue tropism for MPXV
cell tropism (Arthur et al., 2022). However, specific virus ligands remain
unidentified. The inability to identify specific virus ligands and
Despite the name, monkeypox, monkeys are not the genuine cognate host receptors for MPXV tropism suggests that the virus
reservoir of MPXV. Several animals can naturally or experimentally uses many alternative ligands to successfully invade host cells or the
be infected with MPXV (Table 1) (Li et al., 2023), but the natural host receptors have functional redundancy to the virus ligand.

B C

FIGURE 2
Timeline of MPXV re-emergence and global spread. (A) Global map of 2022 mpox of the geographical distribution of the outbreak as of December
5, 2022 (Durski et al., 2018; World Health Organization, 2022). The names of countries with at least one case pre-2022 are labelled. (B) Global maps
zoom on Europe. (C) Weekly cumulative number of cases reported to World Health Organization (WHO) stacked by WHO region. The line/dot
represents the cumulative number of countries affected. Countries: Cameroon (CMR), the Central African Republic (CAR), Cote d’Ivoire (CIV), the
Democratic Republic of the Congo (DRC), Gabon (GAB), the United Kingdom (GBR), Liberia (LBR), Nigeria (NGA), Israel (ISR), Sierra Leone (SLE),
Singapore (SGP), the Republic of the Congo (COD), South Sudan (SSD), the United States of America (USA).

Frontiers in Cellular and Infection Microbiology 03 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

TABLE 1 List of natural MPXV-infected animals and experimental MPXV-infected animals.

MPXV HOST RANGE & RESERVOIR HOSTS

Natural MPXV-Infected Animals References Experimental MPXV- References
Infected Animals
(Alakunle et al., 2020) Prairie (Parker and Buller, 2013; Domá n et al., 2022)
Sooty mangabey monkey (Cercocebusatys)
Dog (Cynomysludovicianus)

Gambian-pouched rat (Cricetomysgambianus) (Alakunle et al., 2020) Mouse (BALB/c and C57BL/6) (Parker and Buller, 2013; Domá n et al., 2022)

(Alakunle et al., 2020) Gambian Pouched (Parker and Buller, 2013)

Rhesus macaques (Macacamulatta)
Rat (Cricetomysgambianus)

(Alakunle et al., 2020) Crowned monkeys (Parker and Buller, 2013)

Cynomolgus macaque (Macacafascicularis)
(Cercopithecus ascanius)

(Alakunle et al., 2020) Red-tailed monkeys (Parker and Buller, 2013)

Asian Monkeys (M. fascicularis)
(Cercopithecus pogonias)

(Alakunle et al., 2020) White-nosed monkeys (Parker and Buller, 2013)

Southern opossum (Didelphis marsupialis)
(Cercopithecus petaurista)

(Alakunle et al., 2020) Western colobus monkey (Parker and Buller, 2013)
Sun squirrel (Heliosciurussp.)
(Colobus badius)

(Alakunle et al., 2020) Rhesus (Parker and Buller, 2013)

African hedgehogs (Atelerixsp.)
macaque (Macacamulatta)

(Alakunle et al., 2020) Cynomolgus (Parker and Buller, 2013)

Jerboas (Jaculussp.)
macaque (Macacafascicularis)

(Alakunle et al., 2020) Thomas’s rope (Parker and Buller, 2013)

Woodchucks (Marmota monax) squirrel
(Funisciurusanerythrus)

(Alakunle et al., 2020) Red-legged sun (Parker and Buller, 2013)

Shot-tailed opossum (Monodelphisdomestica) squirrel
(Heliosciurusrufobrachium)

(Alakunle et al., 2020) Ribboned rope (Parker and Buller, 2013)

Porcupines (Atherurusafricanus) squirrel
(Funisciuruslemniscatus)

(Alakunle et al., 2020) Gambian sun (Parker and Buller, 2013)

Giant anteaters (Myrmecophagatridactyla) squirrel
(Heliosciurusgambianus)

(Alakunle et al., 2020) Eurasia red squirrels (Parker and Buller, 2013)
Prairie dogs (Cynomysspp.)
(Sciurus vulgaris)

(Alakunle et al., 2020) Thirteen-lined ground (Parker and Buller, 2013)

Elephant shrew (Petrodromustetradactylus) squirrel
(Spermophilustridecemlineatus)

Domestic pig (Susscrofa) (Alakunle et al., 2020) Rabbits (Parker and Buller, 2013)

Rope squirrel (Funisciurussp.) (Alakunle et al., 2020) Mouse (CAST/EiJ strain) (Parker and Buller, 2013)

African dormice (Graphiurusspp.) (Alakunle et al., 2020) Cotton rats (Sigmodon sp.) (Parker and Buller, 2013)

Spillover to humans (zoonotic transmission) might arise from the 3 Genomics, phylogenomics,
disruptions of the natural habitats of wild animals (Domá n et al.,
2022). This could occur via various routes, including aerosol, direct
phylodynamics, and evolution
contact, and fomite transmission (Walker, 2022). It is believed that 3.1 MPXV genome and gene content
the MPXV outbreaks in Africa prior to 2022 occurred as a result of a
spillover from animals to humans (Faye et al., 2018; Kabuga and El MPXV has a long and complex genome of 196 Kbp - 211 Kbp
Zowalaty, 2019; Petersen et al., 2019b; Happi et al., 2022; Riopelle with a conserved central region and variable inverted terminal
et al., 2022). Thus, there is a likelihood of MPXV being sustained in repeats (ITR) (Figure 3A). Within MPXV clades, Clade I isolates
the spillover due to the wide geographical coverage of the MPXV have more uniform genome length (196 Kbp - 199 Kbp) than Clade
hosts (Tu, 2015). II isolates (196 Kbp - 211 Kbp). The length of MXPV ITR varies

Frontiers in Cellular and Infection Microbiology 04 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

between 6.5 Kbp to 17.5 Kbp (Shchelkunov et al., 2002; Likos et al., signal in the dataset (R=0.65). Maximum Clade Credibility (MCC)
2005; Nakazawa et al., 2013). Our genomic comparison of MPXV tree (Figure 3C) demonstrated that MPXV emerged at 1730 (95%
clades (Clade I, n=23; Clade IIa, n=13 and Clade IIb, n=161) high posterior density interval (HPD), 1663 – 1790) with a mean
indicated similar gene synteny (excluding the ITR), but slight evolutionary rate estimated to be 5.68 × 10−6 (subs/site/year), with
differences in the gene content among the clades due to some 95% HPD of 4.53 × 10−6 − 6.86 × 10−6 subs/site/year. A recent
genes that are missing or truncated in either one or two clades. The publication estimated the substitution rate to be 5 x 10-6 (Dumonteil
results are consistent with a previous study (Forni et al., 2022a) et al., 2023) which is in agreement with our result, but previous
which indicates that four genes (D14L, D15L, D16L and D17L) are estimations of the substitution rates of Clades I and IIa were smaller
missing and three genes (D4L, B14L and B15L) are truncated in (Gigante et al., 2022). Clades I, IIa, and IIb were estimated to have
Clade II. Furthermore, the homologue of VACV-Cop E5R is only emerged in 1956, 1928, and 1938, respectively which is earlier by 33,
absent in Clade I and three genes (K1R, homologues of VACV-Cop 47, and 97 years as estimated by Forni et al. (Forni et al., 2022b).
A47L and VACV-Cop B11R) are truncated. Another major Lineage A and B.1 were estimated to have a tMRCA of 1998 (95%
difference is the gene content of their left terminal in which Clade HPD, 1990 - 2006) and 2016 (95% HPD, 2014 – 2018), respectively.
IIa contains four genes (N3R, N2R, N1R and R1R) that are absent in Our dating analysis put the emergence of the B.1 lineage six years
Clade I and IIb. However, these four genes are present on the right earlier than that estimated by Luna et al. (Luna et al., 2022) and
terminal of all clades. Furthermore, Clade I and IIb have theD2L Nextclade (https://clades.nextstrain.org/). This discrepancy may be
gene. Within Clade IIb, gene content of the lineage A and B.1 explained by molecular dating methods used (ML-TSP versus BI-
are similar. MCC). We hypothesize that the emergence of lineage A about 1998
allowed enough time for lineage A evolution and that may explain
the long divergent branch length from lineage A to B.1. Similarly,
3.2 Phylogenomics and phylodynamics the emergence of lineage B.1 in 2016 in tandem with clustering of
some 2022 isolates within the lineage A (2017-2019) support cryptic
Our Bayesian phylogenetic (BI) analysis of 62 non-recombinant transmission of the B.1 viruses prior to the current 2022 outbreak in
conserved genes (Diaz-Cá nova et al., 2022a) from 197 MPXV multiple non-endemic countries (Alakunle and Okeke, 2022;
isolates resolved MPXV into three monophyletic clades, namely Dumonteil et al., 2023). A recent molecular clock analysis based
Clade I (Congo Basin Clade), Clade IIa (West Africa Clade) and on accumulation of APOBEC3 (apolipoprotein B mRNA editing
Clade IIb consisting majorly of human MPXV (hMPXV) isolated enzyme, catalytic polypetide 3)-type mutations inferred that MPXV
between 2017-2022 (Figure 3B). Clade IIb was further divided into with APOBEC3 editing has been in circulation since at least 2016
lineages: A (n=11), A.1 (n=11), A.2 (n=1), A.3 (n=1), and B.1 (O’Toole et al., 2023), and this is in agreement with our molecular
(n=135) as assigned by the GISAID (Global Initiative on Sharing All dating reported herein although their interpretation differs from
Influenza Data) (https://gisaid.org/). MPXV tree topology reported ours. While we infer that B.1 lineage emerged in 2016, O`Toole et al.
here is similar to that of the trees reported previously (Gigante et al., concluded that APOBEC3-type mutations, a predictor of human-
2022; Isidro et al., 2022; Luna et al., 2022; Wang et al., 2022). Isidro to-human transmission emerged in 2016. The close phylogenetic
et al. reported that the transition from A.1/A.1.1 to B.1 is relationship between A.1 isolates from Nigeria (in particular
characterized by a long, divergent branch (Isidro et al., 2022) EPI_ISL_15370077) with B.1 suggests a single origin for lineage B.1.
which suggests accelerated microevolution. The findings of this
current study (Figure 3B) agree with the suggestion.
Lineage A (hMPXV-1A) corresponds to the 2017–2019 3.3 Mutational analysis and recombination
outbreak, although it contains strains isolated after this time
frame (Figure 3B) and this observation has been reported by Our mutational analysis revealed that lineage B.1 has 66-86
others (Gigante et al., 2022). A recent study showed that new nucleotide substitutions (60 consensus) and 28-39 amino acid
Nigerian hMPXV genomes isolated in 2019-2020 were identified as substitutions (26 consensus) compared to reference genome
belonging to the lineage A (Ndodo et al., 2023). Lineage B.1 NC_063383.1, MPXV from 2018 (Figures 3D, E). Consensus
contains most hMPXV genomes from 2022 (Figure 3B). It is substitutions predominantly affect genes responsible for host/
poorly resolved, and its sub-lineages cannot be unequivocally immune modulation and viral replication/transcription
assigned (Figure 3B). The low clade supports are probably due to (Figure 3E). B21R (OPG210) codes for a T cell suppressor; our
very low genetic variability among isolates (Scarpa et al., 2022). analysis demonstrated that this open reading frame (ORF)
Polytomy within lineage B.1 could be an indication of uncertainty in contained three consensus amino acid substitutions (D209N,
the relatedness of isolates or the belief that those isolates evolved P722S, and M1741I). A18R (OPG145) contained three
independently from a single origin (Slowinski, 2001; Phylogenetic substitutions (E62K, R243Q, and E435K). Excluding G8R
pitchforks - Understanding Evolution, 2023), although (OPG093) with two substitutions, all the other affected ORFs
recombination cannot be excluded (Yeh et al., 2022). contained one consensus amino acid substitution each
Furthermore, molecular dating analysis was carried out on the (Figure 3E). The impact of these substitutions on the
62 non-recombinant conserved genes of 197 MPXV isolates to pathogenicity, transmissibility, immune evasion, and host
estimate the evolutionary rate and the time of the Most Recent specificity of MPXV remains unknown. The E353K substitution
Ancestor (tMRCA) (Figure 3C). TempEst analysis showed temporal within F13L (OPG057) affects the target for the antiviral agent,

Frontiers in Cellular and Infection Microbiology 05 frontiersin.org

Frontiers in Cellular and Infection Microbiology

Alakunle et al.
A B C

D E
06

FIGURE 3
Genome annotation, phylogenomic tree, maximum clade credibility tree, and mutation map of MPXV. (A) Schematic presentation of MPXV genome. Annotation is given for MPXV reference strain NC_063383.1. The orientation of
ORFs is given by the direction of arrow heads. ORFs are named according to the nomenclature of orthopoxvirus genes (example: OPG001) (Senkevich et al., 2021) and VACV Western Reserve nomenclature (example: J1L). MPXV
genome consists of a conserved central region (OPG048 to OPG151) flanked by variable terminal regions, which contain inverted terminal repeats (ITR) (Shchelkunov et al., 2001; Shen-Gunther et al., 2023). The central region
encodes genes for genome replication, essential enzymes, and structural proteins. Conversely, the variable terminal regions contain mainly virulence and host-range genes (Shchelkunov et al., 2001). MPXV genome encompasses
>190 nonoverlapping open reading frames (ORFs) (Shchelkunov et al., 2001; Hendrickson et al., 2010; Shen-Gunther et al., 2023) and at least 4 ORFs are located in ITR (Shchelkunov et al., 2002; Likos et al., 2005; Nakazawa et al.,
2013). ORFs are colored based on their function. (B) Bayesian Inference phylogenetic tree of concatenated 62 non-recombinant conserved genes from 197 MPXV genomes retrieved from GenBank and GISAID. Recombination

10.3389/fcimb.2024.1360586
detection program 4 (RDP4) (Martin et al., 2015) was used to detect recombination in the 62 conserved genes (Diaz-Cá nova et al., 2022a) and the phylogenetic tree was reconstructed using MrBayes v3.2.7 (Ronquist et al., 2012),
as previously published (Diaz-Cá nova et al., 2022a). Black squares at the nodes indicate posterior probabilities ≥ 0.95. The scale bar represents expected substitutions per site. (C) Time-Scaled Bayesian Inference phylogenetic tree
of concatenated 62 non-recombinant conserved genes from 197 MPXV strains. The presence of a temporal signal within the dataset was examined by regression of genetic divergence (root-to-tip genetic distance) and the
sampling date using TempEst v.1.5.3 (Rambaut et al., 2016). The Maximum likelihood tree of 62 non-recombinant conserved genes built as described previously (Diaz-Cá nova et al., 2022a) was used for TempEst. The maximum-
clade-credibility (MCC) tree was generated using BEAST 1.10.4 (Suchard et al., 2018), using a log-normal strict clock, constant population size, and HKY substitution model. Markov Chain Monte Carlo (MCMC) chains were run until
frontiersin.org

reaching convergence. The convergence of MCMC chains was checked by the effective sample size (ESS) values >200 for each parameter (after burn-in) using Tracer v1.7.1 (Rambaut et al., 2018). The maximum-clade-credibility
(MCC) tree was generated using TreeAnnotator v1.10.4. Black circles at the nodes indicate posterior probabilities ≥ 0.9. The scale bar represents expected substitutions per site. (D) Mutation map showing all 60 consensus
substitutions. 51 of the 60 consensus nucleotide substitutions possessing APOBEC3 like pattern of mutation (GA > AA, GG > AG, and TC > TT). Twenty-eight of these were GA > AA substitutions, two were GG > AG (this
mutational pattern is a product of APOBEC3G), twenty-one were TC > TT, and the remaining nine substitutions were not typical of APOBEC3 editing. (E) Synonymous and non-synonymous mutational count.
Alakunle et al. 10.3389/fcimb.2024.1360586

tecovirimat; however, functional studies have not revealed any effect and structurally indistinguishable. Morphogenesis and
on the efficacy of the drug (Gigante et al., 2022). Wang et al. also transmission of IMV, CEV, and EEV are described in Figure 4A.
reported three mutations in OPG210 protein in MPXV 2022 Observations of cynomolgus monkeys infected with MPXV
outbreak strains (Wang et al., 2022). Additionally, they showed gave the first indications of the pathogenic role of this virus with
that this protein together with other nine proteins (D2L‐like, intramuscular injection of the virus leading to an intense
OPG023, OPG047, OPG071, OPG105, OPG109, A27L‐like, inflammatory immune response (Wenner et al., 1968, 1969). The
OPG153, and OPG188 proteins) have more mutations compared pathogenesis of MPXV has also been studied in other animals,
to the other MPXV proteins (Wang et al., 2022). including rabbits, rodents and prairie dogs (Hutson et al., 2009;
In contrast to our study, previous mutational studies have Bunge et al., 2022). Studies in monkeys, mice, and prairie dogs
reported fewer consensus substitutions (Isidro et al., 2022; Wang demonstrated that Clade I viruses are more virulent than Clade II
et al., 2022; Wassenaar et al., 2022). They reported 46 shared strains, which reflects the situation in humans (Saijo et al., 2009;
mutations in MPXV genomes from 2022 outbreak compared with Hutson et al., 2010; Bunge et al., 2022; Americo et al., 2023;
NC_063383 (Chen et al., 2005; Isidro et al., 2022). However the Falendysz et al., 2023). Except for disease severity, the clinical
number of mutations identified here and in other studies is higher features of the two clades are similar (Kipkorir et al., 2022).
than one would expect for MPXV (Chen et al., 2005; Isidro et al., MPXV infection has an incubation period of 5–21 days and the
2022; Ndodo et al., 2023), based on the low substitution rate of OPXV most common symptoms for the 2022 human mpox outbreak in
(Firth et al., 2010). The accelerated evolution of MPXV has been non-endemic regions based on 48,622 patients were skin lesions
attributed to the human APOBEC3 (Isidro et al., 2022; O’Toole and (95%), fever (58%), lymphadenopathy (53%), fatigue/asthenia
Rambaut, 2022; Wang et al., 2022). Since most mutations identified (39%), myalgia (31%), and headache (30%) (Liu et al., 2023).
here (Figure 3D) and elsewhere were GA>AA and TC>TT mutations, Regarding skin lesions, anogenital lesions were most frequent
which are compatible with APOBEC3 activity. APOBEC3 is a (66%), followed by lesions on the trunk/torso (48%), face/head
cytidine deaminase known to play important functions in innate (39%), and extremities (~30%) (Liu et al., 2023). This is in contrast
anti-viral immunity (Harris and Dudley, 2015; Salter et al., 2016). with previous human mpox outbreaks from 1980-2022 where skin
Evidence for the accumulation of APOBEC3 enriched substitutions lesions were most common on the face and extremities (Pourriyahi
in MPXV isolates has been reported since 2017, which corresponds to et al., 2023). Lymphadenopathy, which typically occurs 1-2 days
the detection of lineage A (Gigante et al., 2022). Ever since, every year, before rash, is a distinct feature of MPXV which is used to
there has been an increase in APOBEC3-like mutations in MPXV distinguish it from smallpox and chickenpox (Altindis et al.,
(Ndodo et al., 2023). This mutational pattern has become more 2022; McCarthy, 2022). The morphological progression of the
pronounced as suggested from more recent isolates (B.1) (Gigante rash is macular, popular, vesicular, and pustular lesions. The crust
et al., 2022; Ndodo et al., 2023), (Figure 3D). The recent pattern of formed by pustules desquamate after 1-2 weeks (Altindis et al.,
upsurge of APOBEC3 derived mutations may be an indication of a 2022; McCarthy, 2022; Nakhaie et al., 2022). In the current
change in virus-host interaction such as sustained human-human outbreak, inguinal lymphadenopathy was more frequent than
transmission (Ndodo et al., 2023) or a new route of infection (Gigante cervical and axillary lymphadenopathy (Liu et al., 2023), whereas
et al., 2022). Gigante et al. (Gigante et al., 2022) suggested the in previous outbreaks in endemic countries submandibular, cervical
possibility of recombination in MPXV following observation of and axillary lymphadenopathy were more frequent (Damon, 2011).
three sequences that showed a chimeric pattern in their genomes, The differences in clinical symptoms between human mpox
although assembly errors could be a plausible explanation. Recently, infections before 2022 and the current outbreak are probably the
tandem repeats and linkage disequilibrium analysis provided result of different virus strain (Clade I versus Clade II, respectively)
evidence of natural recombination in lineage B.1 (Yeh et al., 2022). and patient group (both female and male youngsters versus mainly
adult men having sex with men). In men having sex with men
(MSM), atypical clinical symptoms such as genital lesions and anal
4 Infection biology ulcers were observed (Mitjà et al., 2022; Bragazzi et al., 2023).
and pathophysiology MPXV can enter the host via the oral/respiratory tract, infecting
the oral and respiratory tract mucosae, with the upper, middle and
4.1 Virus morphogenesis, pathogenesis lower airway epithelium as main targets for primary infection (Giulio
and pathophysiology and Eckburg, 2004; Damon, 2011; Kipkorir et al., 2022; Mitjà et al.,
2022). MPXV can directly infect damaged skin, and replicate in
Poxvirus mature particles are ovoid or brick-shaped with keratinocytes, fibroblasts, and endothelial cells (Mitjà et al., 2022).
surface tubules and have a characteristic dumbbell-shaped From the initial infection sites, virus can spread to draining lymph
nucleoprotein core containing the viral genome (Shchelkunov nodes, where the virus can replicate. MPXV can subsequently reach
et al., 2001). MPXV virions are ~200 nm in diameter and ~300 the tonsils, the spleen, and the liver. Replication in these organs
nm in length (Wenner et al., 1968). Like other OPXVs, MPXV results in a second viraemia wave, enabling the virus to access distant
forms three distinct infectious virus particles: intracellular mature organs such as the lung, kidneys, intestines, and skin and causing
virus (IMV), cell associated enveloped virus (CEV) and extracellular recognizable clinical manifestation (Giulio and Eckburg, 2004;
enveloped virus (EEV) although CEV and EEV are morphologically Damon, 2011; Kipkorir et al., 2022; Mitjà et al., 2022).

Frontiers in Cellular and Infection Microbiology 07 frontiersin.org

Frontiers in Cellular and Infection Microbiology

Alakunle et al.
A B

C
08

FIGURE 4
MPXV morphogenesis, signaling and immune evasion strategies. (A) The MPXV replication cycle. After attachment of the virion to the host cell membrane, the viral genome is released by uncoating followed by transcription and
duplication of the viral genome. Translation and subsequent assembly results in IMV. MPXV virions can exist as intracellular mature virus (IMV), cell associated enveloped virus (CEV) and extracellular-enveloped virus (EEV). IMV assembles in
the cytoplasm and consists of a core particle wrapped in a membrane. IMV particles egress from the infected cells by lysis, whereas some IMVs are transported through microtubules and wrapped by an intracellular membrane to
produce an intracellular enveloped virus (IEV), which can further fuse with the cell membrane and be released to form EEV (Schmidt and Mercer, 2012; Sivan et al., 2016; Realegeno et al., 2020). Some EEVs remain attached to the cell
surface (CEV) and are responsible for cell-to-cell spread, whereas EEV that detaches from the infected cells play a role in long-range dissemination within the host (Blasco and Moss, 1992). IMV particles are thought to be the form
responsible for inter-host viral transmission. In contrast, EEV are known to be important for intra-host viral dissemination (Payne, 1980). (B) MPXV strategies to activate signaling pathways. Left panel: The canonical NFkB pathway requires

10.3389/fcimb.2024.1360586
activation of the cytoplasmic p65/p50 dimer, which is anchored into the cytoplasm through its interaction with IKa. The trimer IKKa/IKKb/IKKg will upon activation phosphorylate IKa, which is subsequently ubiquitinated and probed for
proteasomal degradation. This results in release of p65/p50, which translocate to the nucleus and can induce transcription of NFkB target genes. Several MPXV proteins can perturb the NFkB pathway. Right panel: The JAK/STAT pathway
consist of the tyrosine kinases JAK that phosphorylate and activate the transcription factor STAT. The MPXV proteins encoded by the genes H1L and D11L can inhibit activation of the JAK/STAT pathway. (C) MPXV avoids detection of
virus-infection cells by cytotoxic CD8+T cells. Infected host cells will present viral peptide fragments by MHC-I molecules. These will be recognized by T cell receptors (TCR). Co-recognition of NKG2D ligand on the MPXV-infected cell
and the NKG2D receptor on the CD8+ T cell is required. MPXV will prevent the latter interaction by expressing soluble NKG2D. Moreover, the cytokine gradient produced upon MPXV infection will be disturbed by MPXV-encoded
proteins that will bind these cytokines such as TNFa, IL-1b.
frontiersin.org
Alakunle et al. 10.3389/fcimb.2024.1360586

Comparison of the Clade I and II strains has provided an aa polypeptide with unknown function) (Kugelman et al., 2014).
indication which viral gene products may be responsible for OMPC functions as soluble natural killer group 2, member D
their difference in virulence. The D14L gene which encodes receptor (NKG2D) ligand, possibly representing a strategy to
valosin-containing protein (VCP)-MPXV, also known as CCP avoid NK-cell-mediated killing (Campbell et al., 2007; Lazear
or MOPICE, is the orthologue of VACV secreted complement et al., 2013). Based on the clinical metadata, it was suggested that
C3b/C4b-binding protein VACV-Cop C3L (Chen et al., 2005). the deletion is associated with increased human-to-human
This protein is known to inhibit the complement and to contribute transmission and pathogenicity compared to Clade IIa and Clade
to virulence (Kotwal et al., 1990; Isaacs et al., 1992). Compared to IIb isolates (Forni et al., 2022a).
the VACV protein, VCP-MPXV/MOPICE is truncated due to a The Clade I strain also contains truncated orthologues of
single nucleotide deletion in the D14L gene leading to a stop VACV-Cop E3L and VACV-Cop K3L, two proteins that function
codon (Uvarova and Shchelkunov, 2001). The gene is absent from in interferon (IFN) resistance (Weaver and Isaacs, 2008). Clade I
Clade II strains due to ~10 kbp deletion (Likos et al., 2005). and Clade II genomes differ also in VACV-CopH5R (the VACV
Deletion of the C3L gene caused VACV attenuation in infected orthologue encodes a late transcription factor, which plays a role in
animal models (Isaacs et al., 1992; DeHaven et al., 2010; Girgis viral replication, transcription and morphogenesis (Van Vliet et al.,
et al., 2011). Studies with Clade I MPXV with deleted D14L 2009), VACV-Cop A9L (VACV orthologue encodes a
showed that intranasal infection of prairie dogs resulted in morphogenesis factor) (Van Vliet et al., 2009), VACV-Cop A50R
decreased morbidity and mortality. However, ablation of D14L (VACV orthologue encodes a DNA ligase) (Van Vliet et al., 2009)),
did not significantly affect virus replication compared to animals and VACV-Cop A36R (playing role in actin tail formation) (Wolffe
infected with control Clade I virus. On the other hand, Clade II et al., 1998)). The exact mechanisms by which these proteins may
virus with inserted D14L gene did not have virulence compared to also contribute to differences in pathogenicity between Clade I and
Clade I virus and no apparent effect on disease-associated II strains remains elusive.
mortality compared to control Clade II virus was observed
(Hudson et al., 2012). So, other factors besides VCP-MPXV/
MOPICE are necessary to explain the difference in virulence 4.2 Signal transduction and pathways
between Clade I and II MPXV.
Other candidate virulence genes include BR-203, BR-209, and Manipulation of signaling pathways promotes viral replication
the OPXV major histocompatibility complex class I–like protein and determines disease outcomes, mainly by targeting cell growth
orthologue (OMCP or N3R) (Chen et al., 2005; Likos et al., 2005). and immune responses (Krajcsi and Wold, 1998; Greber, 2002).
BR-203 protein is an orthologue to the myxoma virus M-T4, which MPXV infection suppresses expression of host genes whose
plays a role in avoiding apoptosis of infected lymphocytes, hence products are implicated in regulation of histone expression,
promoting viral spread within the host (Barry et al., 1997; Weaver cytoskeletal rearrangements, cell cycle progression, IFN-associated
and Isaacs, 2008). Myxoma virus expressing C-terminal truncated genes, and signaling pathways such as the nuclear factor kappa B
M-T4 caused increased inflammatory response compared to rabbits (NFkB), the mitogen-activated protein kinase (MAPK), and
infected with wildtype virus, whereas challenging with virus lacking metabolic pathways (Alkhalil et al., 2010; Rubins et al., 2011;
M-T4 resulted in disease attenuation (Barry et al., 1997; Hnatiuk Xuan et al., 2022).
et al., 1999). Thus, BR-203 may have a dual function in protecting The NFkB pathway plays pivotal roles in inflammation and
infected lymphocytes from apoptosis and in modulating the immunity (Shao-Cong Sun, 2017). NFkB is typically found as a
inflammatory response to virus infection. cytosolic trimer of p65/p50 and the inhibitor protein IkB.
The BR-209 gene encodes a 326 aa interleukin-1b (IL-1b) binding Phosphorylation of IkB by the trimer IKKa/IKKb/IKKg results in
protein, which prevents IL-1b from interacting with the IL-1 receptor. the release and activation of p65/p50, which translocate to the
Mice intranasally infected with VACV lacking IL-1b binding protein nucleus and act as a transcription factor (Hayden and Ghosh, 2008)
developed a more severe illness than wildtype virus (Alcami and Smith, (Figure 4B). Ankyrin proteins from OPXVs can inhibit the NFkB
1992). Perturbing the IL-1 signaling pathway dampens the innate and pathway by interfering with different components of this pathway
acquired immunity, explaining the virulent action of the IL-1b binding (Shisler and Jin, 2004; Chen et al., 2008; Mohamed and McFadden,
protein (Dinarello, 2018). Interestingly, the BR-209 gene of Clade I 2009; Ember et al., 2012; Mansur et al., 2013; Herbert et al., 2015).
strains has two ORFs that can encode a putative N-terminal protein MPXV genome encodes the ankyrin-like proteins J3L, D1L, D7L,
fragment of 210 aa and a C-terminal protein fragment of 126 aa, D9L, O1L, C1L, B5R, B17R, N4R, and J1R (Shchelkunov et al., 2002;
whereas the Clade II strains encode a putative N-terminal 163 aa Lum et al., 2022), but their exact function remains to be determined.
polypeptide and a C-terminal 132 aa fragment (Weaver and Isaacs, In addition, the MPXV BCL2-like proteins A47R, B13R, C6R, and
2008). It is unknown if any of the fragments function in a way similar P1L can prevent activation of the NFkB pathway (Lum et al., 2022).
to the full-length protein, nor if the differences in the length of the N- The MPXV B1R gene encodes the VACV Kelch-like protein A55,
terminal fragments of Clade I versus Clade II strains of MPXV which inhibits the NFkB pathway and stimulates CD8+ T cell
contribute to the differences in virulence (Weaver and Isaacs, 2008). proliferation (Lysakova-Devine et al., 2010). However, it remains to
The OMCP gene (N3R) from Clade I strains isolated in the DRC be determined whether B1R exerts a similar function.
carries a 628 bp deletion, which removes the 5’region of the N3R The Janus kinase (JAK) and signal transducer and activator of
gene (which encodes the OMCP) and the N2R gene (encoding a 73 transcription (STAT) pathway mediates cellular responses to

Frontiers in Cellular and Infection Microbiology 09 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

cytokines and growth factors (Mythology, 1990). H1L inactivates Binding of viral dsRNA to specific TLR members triggers the
STAT1, and C6R blocks STAT2 (Mann et al., 2008; Stuart et al., expression of proinflammatory molecules involved in host anti-
2016). Whether the MPXV H1L and D11L orthologues act similarly viral responses and subsequent activation of the adaptive immune
has not been investigated (Figure 4B). defense system (Mogensen, 2009). The VAVC A46 protein inhibits
The VACV epidermal growth factor homologue VGF (C11R) the TLR4 signaling pathway (Lysakova-Devine et al., 2010).
usurps the epidermal growth factor receptor (EGFR) pathway to However, it is unknown whether the MPXV orthologue A47 has
provoke cell proliferation and to stimulate efficient virus spread and the same property, but the A47 protein has structural similarities to
pathogenesis (Buller et al., 1988; Beerli et al., 2019). The D3R gene VACV protein A52R, which can inhibit the TLR3 and TLR4
(OPG019) encodes an EGF homologue that might activate the signaling pathways (Bowie et al., 2000; Harte et al., 2003),
EGFR pathway and enhance viral dissemination. VACV-Cop F11L underscoring a role for MPXV A47 in interfering with TLR
also promotes viral spreading by inhibiting the RhoA signaling signaling. MPXV produces low levels of dsRNA intermediates
pathway (Beerli et al., 2019). It is not known whether the MPXV (Arndt et al., 2016), but whether these are recognized by TLR3
orthologue C17L possesses the same function. has not been investigated, although transcriptome analysis of
Circumventing apoptosis is used by viruses to achieve MPXV-infected cells revealed repression of TLR3 target genes
productive replication. VACV F1L and N1L proteins can prevent (Rubins et al., 2011). dsRNA can also activate kinase R (PKR),
apoptosis by inhibiting pro-apoptotic proteins BAK, BID, BAD, and which mediates phosphorylation of eIF2a, resulting in the
BAX (Aoyagi et al., 2006; Cooray et al., 2007). It is unknown inhibition of viral and cellular mRNA translation (Pears, 1995).
whether the MPXV C7L and P1L isologues have similar functions. VACV E3 and K3 are inhibitors of PKR, allowing VACV to evade
Other MPXV genes that prevent apoptosis include B12R, B19R, an antiviral response (Seet et al., 2003; Deng et al., 2008). The N-
D5R, and F3L (Lum et al., 2022). B12 is a serine protease and its terminal domain of VACV E3 protein is absolutely required for the
VACV orthologue B13R has been shown to be a caspase inhibitor interaction with dsRNA (White and Jacobs, 2012). MPXV F3
(Li and Beg, 2000). protein is the VACV E3 protein homologue with a 37 aa
Signal transduction is often mediated through a cascade of truncation at the amino terminus (Arndt et al., 2015), suggesting
phosphorylation events (Denhardt, 1996). Kindrachuk et al. that MPXV F3 does not bind dsRNA. However, MPXV can inhibit
compared the phosphorylation pattern of host cell proteins after host immune responses, although a recombinant VACV expressing
Clade I or Clade II MPXV infection (Kindrachuk et al., 2012). They the MPXV F3L gene did not inhibit host PKR activation (Arndt
found that Clade I MPXV infection down-regulated pathways et al., 2015), suggesting that MPXV has evolved to encode for yet
related to cell proliferation and apoptosis as compared with Clade undiscovered proteins that compensate for the missing N-terminal
II MPXV. Differences in MPXV-induced posttranslational amino acids of F3 in limiting host antiviral activities. As previously
modification may explain the differences in virulence between mentioned, MPXV CCP (D14L gene) is completely absent in Clade
MPXV clades. II isolates, whereas the Clade I strains are predicted to express CCP,
albeit with a truncated fourth short consensus repeat (Yeh and
Contreras, 2022). Loss of expression of CCP/MOPICE limited the
4.3 Host immune response and virus adaptive immune response against MPXV infection in rhesus
immune decoy mechanisms macaques (Estep et al., 2011).
IFNs are main effectors of the innate immune response and can
4.3.1 Host immune response inhibit virus replication (Seet et al., 2003; Randall and Goodbourn,
Human infection with MPXV is associated with increased levels 2008). The MPXV B16 protein (VACV B19 orthologue) is a
of ILs, C-C motif chemokine ligand 2 (CCL2) and CCL5 (Johnston secreted type I IFN inhibitor and suppresses the antiviral type I
et al., 2015), and a significant decrease in tumor necrosis factor IFN-induced signaling pathway (Ferná ndez de Marco et al., 2010).
alpha (TNF-a), IFN-g, and IL-2 and IL-12 (Li et al., 2022). MPXV VACV K7 abrogates IFN signaling by destabilizing IFN-regulated
infection provokes IgM and IgG antibodies, long-term persistence factor 3 (IRF3) and inhibits NFkB activation, whereas VACV H1
of residual IgG-memory B cells, and a rapid expansion of activated can block IFN signaling (Benfield et al., 2013; Liu and Moss, 2018).
effector CD4+ and CD8+ T cells followed by a decrease over time Whether the MPXV D9 and H1 orthologues have the same function
(Agrati et al., 2022; Mitjà et al., 2022). MPXV also interferes with remains to be proven, but both proteins are predicted to interact
adaptive immune responses of antiviral CD8 + and CD4 + T cell with several cellular proteins of the immune system (Mann et al.,
responses via inhibiting T cell receptor-mediated T cell activation 2008; Kumar et al., 2023). VACV E3 perturbs IFN signaling by
(Hammarlund et al., 2008). binding host Z-DNA binding protein 1 (ZBP1). The MPXV E3
orthologue (F3) perturbs the IFN pathway, but whether in a ZBP1-
4.3.2 Evasion host immune defense dependent manner needs to be established. The DNA-sensing
Because of the high homology between the MPXV genes and receptor pathway cGAS/STING (cyclic GMP-AMP synthase/
the corresponding OPXV orthologues, it is assumed and, in some stimulator of interferon genes) can activate the IFN and NFkB
cases, demonstrated that MPXV applies similar strategies to evade pathways (Motwani et al., 2019). The VACV B16 and B8 proteins
the host immune defense system. The Toll-like receptor (TLR) block IFN signaling by operating as soluble IFN-a and IFN-g
family functions as pattern recognition receptors, which recognize receptors, respectively (Alcamı́ and Smith, 1995; Colamonici
damage-associated molecular patterns such as viral dsRNA. et al., 1995). The MPXV ORF B16R and B9R encode functional

Frontiers in Cellular and Infection Microbiology 10 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

homologues (Shchelkunov et al., 2002). OPXVs encode poxins that MOPICE which from studies with VARV and VACV MOPICE
degrade 2′,3′ cGAMP and thereby inhibit cGAS/STING signaling was found to inhibit activation of the complement pathway
(Eaglesham et al., 2019). Poxin is conserved in MPXV where it is (Liszewski et al., 2006). MOPICE modulates the antiviral immune
fused to an additional C-terminal domain previously noted to have response as observed by enhanced viral replication in vivo and
homology with human schlafen proteins (VACV B2R = MPXV dampened adaptive immune response in rhesus macaques infected
B4R) (Eaglesham et al., 2019), hence MPXV may evade the immune with MPXV lacking MOPICE expression (Estep et al., 2011;
system by targeting the cGAS/STING pathway. Hudson et al., 2012). Because of the absence of the D14L gene in
MPXV can dodge the immune system by targeting the antiviral the Clade II, the virus and virus-infected cells would be predicted to
cytokine TNFa and other immunomodulating molecules. The be susceptible to the host complement attack. However, the
MPXV-encoded cytokine response-modifying protein B (CrmB; expression of MOPICE in Clade II did not increase its virulence
J2L or OPG002) functions as a decoy receptor for TNFa (Gileva (Hudson et al., 2012), demonstrating that MOPICE is not the sole
et al., 2006). The C-terminal domain of VACV CrmB can bind determinant of differences in viral virulence between the two clades.
CCL28, CCL25, CXC motif chemokine ligand 12 (CXCL12), Less is known how MPXV may interfere with the adaptive
CXCL13 and CXCL14 (Alejo et al., 2006). It is unknown whether immune system. MPXV interferes with adaptive immune responses
MPXV CrmB interacts with these chemokines, but the amino acid of antiviral CD8 + and CD4 + T cell responses via inhibiting T cell
sequence of the corresponding domain in MPXV CrmB differs receptor-mediated T cell activation (Hammarlund et al.,
significantly (Gileva et al., 2006). 2008).VACV A35 blocks immune priming of T lymphocytes by
Natural killer (NK) cells and cytotoxic T cells (CTL) play a interfering with MHC class II-restricted antigen presentation.
crucial role in eliminating viral infections. Although the number of Moreover, infection studies in cells with MPXV lacking the A35R
NK cells expand significantly in peripheral blood and lymph nodes gene demonstrated that A35 inhibits production of cytokines and
in MPXV-infected rhesus macaques, their migrating capacity was chemokines (Rehm et al., 2011). MPXV A35 analogue, A37, might
reduced, and several functions such as expression of chemokine suppress presentation of viral antigens to immune cells and help the
receptors (including CCR5, CCR6 and CXCR3) and secretion of virus to evade the host immune defense system. However, MPXV
IFNg and TNFa were impaired (Song et al., 2013). The importance does not seem to interfere with MHC expression or intracellular
of NK cells in controlling MPXV viral load was demonstrated in the transport of MHC molecules (Hammarlund et al., 2008).
highly vulnerable to OPXV infection CAST/EiJ mouse strain owing
to low numbers of NK cells. IL-15 treatment, known to increase the
numbers of IFNg-secreting NK cells and CD8+ T cells, protected 5 Epidemiology
CAST/EiJ mice from lethal MPXV infection even when both CD4+
and CD8+ T cells were depleted. This implies that the expanded NK 5.1 Demographic and
cells were responsible for the protective effect (Al-musa et al., 2022; epidemiological characteristics
Lum et al., 2022).
MPXV protein B10 avoids detection of virus-infected cells by Surveillance data on mpox in endemic countries during
CTL by impairing peptide loading and MHC-I trafficking within the different periods between 1970-2015 showed that 71%-83% of the
endoplasmic reticulum. However, NK cells continually screen cells disease occurred in children (<10 years of age) and 51%-67% in
via NKG2D for the absence of MHC-I, thereby ensuring that the males (Breman et al., 1980; Heymann et al., 1998; Rimoin et al.,
MHC system is not compromised (Lum et al., 2022). MPXV- 2011). In contrast, the median age for the 2017-2018 outbreak in
infected cells with downregulated MHC-I expression overcomes Nigeria was 29 years, with males accounting for 64% of the cases
detection by NK cells by secreting the OCMP protein that binds (Yinka-Ogunleye et al., 2019). However, for the 2022 multi-country
NKG2D and suppress the typical NKG2D-dependent NK cell lysis outbreak, males accounted for 96.8% of the cases, and the median
of cells that do not express MHC-I (Lum et al., 2022) (Figure 4C). age was 34 years (Interquartile range: 29 – 41) (World Health
IL-18, an IFNg-inducing factor, stimulates the synthesis of various Organization., 2022). In the African region, children (0-9 years of
cytokines and chemokines, regulates Th1 and Th2 cell responses, age) accounted for 23.08% of mpox cases compared to <1% in
and activates NK and CTL (Seet et al., 2003). OPXVs block IL-18 Europe and the Americas. Notably, the male-to-female ratio in
activities by producing an IL-18 binding protein (Born et al., 2000). Africa is also markedly lower than in other regions (Figures 5A-C)
The MPXV D6L gene encodes such IL-18 binding protein (World Health Organization, 2022).
(Shchelkunov et al., 2002).
The MPXV J3R and A41L genes encode chemokine binding
proteins (Shchelkunov et al., 2002), which are assumed to destroy 5.2 Case fatality rate
the chemokine concentration gradient resulting in decreased
neutrophil migration in tissues infected with MPXV and thus Before the 2022 outbreak, the overall pooled estimated case
reducing viral virulence and inflammatory response (Bahar fatality rate (CFR) was 8.7% and varied by the clade of the virus
et al., 2008). (Bunge et al., 2022). The pooled CFR for Clade II was 3.6% and
The complement system, which forms an essential part of the 10.6% for Clade I (Bunge et al., 2022). The 2022 outbreak has an
innate immune system is activated early in MPXV infection in mice, estimated CFR of 0.08% (World Health Organization, 2022). The
and is crucial for viral control (Moulton et al., 2008). MPXV low CFR in the current outbreak may be related to several factors,

Frontiers in Cellular and Infection Microbiology 11 frontiersin.org

Frontiers in Cellular and Infection Microbiology

Alakunle et al.
A B C

D
12

10.3389/fcimb.2024.1360586
FIGURE 5
Demographic characteristics and transmission routes of human mpox. Demographic characteristics of 2022 human mpox cases according to sex and age in three WHO regions based on data from 4727328. (A)
African region, (B) European region and (C) region of Americas. The pyramid plots show the number of cases and percentage of overall cases. (D)Transmission of mpox in endemic and non-endemic regions pre-
2022 and 2022 outbreak. The characteristics of outbreaks in the different regions were highlighted. Prior to 2022, mpox was limited to the endemic regions and cases outside the region were usually travel
related. However, the 2022 outbreak in non-endemic region was not travel related and has been reported in several countries.
frontiersin.org
Alakunle et al. 10.3389/fcimb.2024.1360586

including the fact that the Clade II has a CFR of <1%, active those with non-invasive exposure (Reynolds et al., 2018). Dewitt et al.
surveillance, early diagnosis, and treatment (World Health predicted the MPXV mode of transmission in most 2022 studies to be
Organization, 2022b). caused by inter-human transmission (Dewitt et al., 2022) (Figure 5D).
Large respiratory droplets, bodily fluids, contaminated fomites, and
viral shedding through feces are also considered risk factors for viral
5.3 Secondary attack rate transmission (Rimoin et al., 2010; Sklenovská and Van Ranst, 2018; El
Eid et al., 2022). Airborne transmission of MPXV between animals in
Over the past five decades, the secondary attack rate for mpox experimental settings has also been reported and MPXV was detected
has been stable and ranges from 0% to 10.2% (Breman et al., 1977; in upper respiratory samples, suggesting that interhuman transmission
Merouze and Lesoin, 1983; Tchokoteu et al., 1991; McCollum et al., of MPXV via the airborne route may be possible. However,
2014; Besombes et al., 2019; Ye et al., 2019). Higher estimates were epidemiological observations do not support airborne transmission
reported in the 2013 outbreak in the DRC (50% among 16 as the primary route of transmission (Riopelle et al., 2022). The virus
households) and Nigeria (71% in the 2017- 2018 outbreak from a can also cross the placenta, suggesting vertical transmission (Mbala
single household) (Nolen et al., 2015; Beer and Bhargavi Rao, 2019; et al., 2017; Cuerel et al., 2022). At least 12 pregnant women have been
Bunge et al., 2022). However, it is imperative to note that it is infected during the 2022 outbreak, but vertical transmission was not
unclear how the high estimates were obtained and thus may likely observed in any case (Khalil et al., 2020).
be overestimated (Beer and Bhargavi Rao, 2019). MPXV has also been detected in human semen (Antinori et al.,
2022; Noe et al., 2022), and in archival testes tissue of crab-eating
macaque (Liu et al., 2022), suggesting potential sexual transmission
5.4 Virus reproduction number of the virus. Recent outbreak suggests that MSM subpopulation may
also be at an increased risk (Kipkorir et al., 2022).
Reproduction number (R0) is the number of secondary cases In addition, waning immunity against smallpox has been
anticipated to develop from a single primary case in a naive considered another potential risk factor for the disease (Rimoin
population (Beer and Bhargavi Rao, 2019). While historical data et al., 2010). Evidence from early outbreaks in the 1980s showed
on R0 is limited, published evidence from DRC’s active surveillance that previous smallpox vaccination provided 85% protection against
between 1980 and 1984 estimated R0 to be 0.8 (Beer and Bhargavi mpox (Rimoin et al., 2010). Most cases reported were among those
Rao, 2019), implying that transmission is ineffective as a human-to- born after vaccination ceased in 1980, and herd immunity has
human epidemic is likely to die out (Beer and Bhargavi Rao, 2019). significantly decreased (Rimoin et al., 2010).
However, early estimations of the R0 in the 2022 outbreak in non- Evidence from the literature suggests that those who are
endemic countries showed a high variability ranging from 1.54 immunocompromised due to HIV and other underlying conditions
(Belgium) to 3.62 (Germany), with a median of 2.44 (Branda et al., are at increased risk of severe mpox disease (Center for Diseases
2023). This suggests sustained human-to-human transmission, Control and Prevention (CDC), 2022b) (Yinka-Ogunleye et al.,
possibly due to several contributing factors, including different 2019). A high proportion of patients with mpox in the 2022
social and/or sexual behaviors, different MPXV variants, outbreak had concurrent HIV infection and sexually transmitted
population density or other unknown causes (Branda et al., 2023). infections (STI) (Fischer et al., 2022; Ghaffar and Shahnoor, 2022).
While the early estimations indicated sustained transmission, the Mpox patients with HIV infection were more likely to be hospitalized
outbreak has slowed down with case reductions. This could be due than those without HIV infection (Curran et al., 2022). However, the
to behavior change, infection induced immunity, and vaccinations. evidence on the reason for hospitalization is limited, and it is
unknown if it reflects a more severe mpox illness (Curran et al., 2022).
Furthermore, co-infection with other conditions with rashes,
5.5 Risk factors (sexual and social such as a varicella-zoster virus (VZV), can occur (Hughes et al.,
networks, smallpox vaccination) and 2021; Stephen et al., 2022). This herpesvirus causes chickenpox and
co-morbidities shingles and is frequently misdiagnosed as mpox in regions where
both diseases are endemic (Hoff et al., 2017; Hughes et al., 2021).
Transmission of MPXV can occur from animal-to-human Chickenpox is exclusive to humans and more common in younger
(zoonotic) and from human-to-human (interhuman). Zoonotic age groups, and co-infection with mpox has been reported more
transmission usually happens through contact with an infected commonly among children (Leung et al., 2019; Hughes et al., 2021).
animal’s bodily fluid or through a bite or scratch (Reynolds et al.,
2007). Exposure to animal reservoirs, especially in regions with
deforestation enhancing animal-human contact, and uncooked meat 6 Diagnosis, screening, prevention,
products are major risk factors for zoonotic transmission (Kipkorir and treatment
et al., 2022). During the 2003 USA outbreak, exposure was classified as
“non-invasive” (touching an infected animal) or “complex” (invasive 6.1 Diagnosis and case definitions
bite from an ill animal; non-invasive exposure i.e., any exposure that
did not break the skin) (Reynolds et al., 2018). Patients with complex Electron microscopy, immunohistochemical detection of
exposures were more likely to develop systemic illness compared to MPXV proteins, and detectable levels of anti-OPXV IgM

Frontiers in Cellular and Infection Microbiology 13 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

antibody during the period of 4 to 56 days after rash onset can be been associated with the vaccine (Chandran et al., 2022). Therefore, the
used to diagnose MPXV infection, but all methods are not specific vaccine is no longer licensed by European Union (Luo and Han, 2022).
(Center for Diseases Control and Prevention (CDC), 2022a). JYNNEOS (Imvamune or Imvanex) was approved by FDA in
According to the Centers for Disease Control and Prevention September 2019 for prevention of smallpox and mpox in adults
(CDC) (Center for Diseases Control and Prevention (CDC), aged >18years (Alakunle et al., 2020). JYNNEOS is the brand name
2022a), mpox cases should be confirmed by real-time polymerase of Modified Vaccinia virus Ankara Bavarian Nordic (MVA-BN)
chain reaction (qPCR) or Next-Generation sequencing and vaccine (Kmiec and Kirchhoff, 2022), a non-replicating third-
isolation of MPXV in culture from a clinical specimen. The F3L, generation attenuated vaccine. JYNNEOS is considered safer
E9L, B6R and J2R genes are all target of qPCR in MPXV diagnosis ( wi th proven e ffic a c y i n a n i m a l s an d h u m a n s ) th a n
(Li et al., 2010; Alakunle et al., 2020; Altindis et al., 2022; Cheema ACAM2000™ (Sah et al., 2022a). The Advisory Committee on
et al., 2022; Nakhaie et al., 2022). The suspected mpox cases are Immunization Practices has recommended JYNNEOS as an
characterized by fulfilling one of the epidemiological criteria (within alternative to ACAM2000™ (Harapan et al., 2022). Nonetheless,
21 days of illness onset), as outlined by CDC (Center for Diseases both vaccines (JYNNEOS and ACAM2000 ™ ) have been
Control and Prevention (CDC), 2022a). recommended for MPXV high-risk groups (Petersen et al., 2022).
LC16m8 is another potential vaccine for MPXV which is
obtained by subjecting VACV lister to 36 serial passages at low
6.2 Surveillance and contact tracing temperature (30°C) in primary rabbit kidney cells (Domá n et al.,
2022; Poland et al., 2022; Schnierle, 2022). As a third-generation
One of the crucial ways of controlling the spread of mpox is attenuated vaccine (Gessain et al., 2022), LC16m8 has been shown to
contact tracing (Harapan et al., 2022; Kalyar et al., 2022). Individuals be protective against MPXV in animal models with lower
exposed to MPXV should be monitored for 21 days checking mpox neurotoxicity (Domá n et al., 2022; Schnierle, 2022). The frameshift
symptoms, and those with suspected or confirmed mpox cases should mutation in LC16m8’s major extracellular enveloped virion antigen
be isolated to avoid infecting others (Titanji et al., 2022). Velavan (B5R) contributes to the vaccine replication competence and low
et al. predicted the mpox outbreak would not last provided that cases virulence (Domá n et al., 2022). Presently, LC16m8 is only licensed in
are well isolated through the contact tracing (Velavan and Meyer, Japan (Domá n et al., 2022; Schnierle, 2022).
2022). Although much attention is given to human-human contact
tracing, great efforts need to be put into animal-animal and animal-
human contact tracing especially due to non-specificity of reservoir 6.4 Antivirals
hosts for MPXV (Petersen et al., 2019a). Surveillance cannot be
undermined in curtailing mpox as surveillance would provide more Although there are no specific antivirals for mpox, some
insight into the epidemiology of the disease (Riopelle et al., 2022). In antivirals (tecovirimat, brincidofovir, cidofovir) have been explored
Nigeria, the Outbreak Response Management and Analysis System (Riopelle et al., 2022). Tecovirimat (ST-246 or TPOXX®), 4-
(SORMAS) for mpox surveillance across portions of 8 states was trifluoromethylphenol derivative, was approved (for smallpox) by
implemented in November 2017 for the mpox outbreak. The use of FDA in 2018 and approved by European Medicines Agency in
the system increased the quantity of epidemiological data collected January 2022 for treatment of smallpox and cowpox. Tecovirimat
and the communication of aggregate case data (Mauldin et al., 2022). inhibits VP37 (p37) protein of VACV by targeting the viral F13L gene
(Frenois-Veyrat et al., 2022) and the CPXV homolog V016 gene
(Siegrist and Sassine, 2022). VP37, a highly conserved protein in
6.3 Vaccine OPXV genus, is required for viral maturation and release from the
infected cell. Inhibition of VP37 prevents viral spread within an
Although there is no specific vaccine for MPXV (Hobson et al., infected animal models (Rizk et al., 2022). Goyal etal. recommended
2021; Sah et al., 2022a), the smallpox vaccines have been reported to tecovirimat to be administered as first line of mpox treatment in
give 85% cross-immunity against MPXV due to shared antigenic pregnant and breastfeeding patients (Goyal et al., 2022). A
features (Alakunle et al., 2020). tecovirimat analogue (synthesized by the State Research Center of
ACAM2000™ is a replication-competent vaccinia virus vaccine Virology and Biotechnology, Russia) has been highlighted as a
licensed by Food and Drug Administration (FDA) in August 2007 for promising antivirals against OPXV infections (Singhal et al., 2022).
smallpox prevention, and it is derived from a single clonal viral isolate Cidofovir (CDV or Vistide®) prodrug is an acyclic nucleoside
from Dryvax (Gruber, 2022; Poland et al., 2022) which is a first- phosphate (Alakunle et al., 2020) that was approved by FDA in 1996
generation smallpox vaccine. As a second-generation attenuated for the treatment of retinitis (caused by cytomegalovirus) in AIDS
vaccinia virus vaccine (Gessain et al., 2022), ACAM2000™ has been patients (Harapan et al., 2022). The efficacy of CDV has been
recommended as MPXV post-exposure prophylaxis (Aden et al., 2022; identified during the in vitro studies in MPXV-infected animals, but
McCarthy, 2022). Although high level of protection against mpox in the clinical data of CDV efficacy against mpox in human are not
animal models has been recorded, the safety of ACAM2000™ in available. Brincidofovir (CMX001 or hexadecyloxypropyl-
humans is still of great concern as cardiac complications, and extremely cidofovir), a CDV derivative, was approved for smallpox
painful and uncomfortable cutaneous reaction at the injection site have treatment in 2021 by FDA, and it has lesser toxic effects than

Frontiers in Cellular and Infection Microbiology 14 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

CDV (Ortiz-Saavedra et al., 2022). Evaluation of CMX001 efficacy linking the mpox 2022 outbreak to Africa/West Africa/Nigeria is
and safety in human mpox through the clinical trials is needed worrisome (Sousa et al., 2022). Despite the mpox 2022 outbreak,
(Ortiz-Saavedra et al., 2022; Siegrist and Sassine, 2022). which occurred outside Africa, the nomenclature and the geographical
labels of MPXV strains still reference West African, even though the
origin of this outbreak is still unresolved. Furthermore, high mpox cases
7 Biosafety, Biosecurity and Bioethics were reported among MSM (Happi et al., 2022; Malta et al., 2022; Sousa
et al., 2022; Sah et al., 2022b). This narrative portrays these men
7.1 Recombination with vaccinia virus and contracting MPXV because they engaged in sexual intercourse with
other OPXV fellow men, meanwhile the spread of the virus can occur regardless the
sex. Vaccine inequality affects lower- and middle-income countries
Due to inadequate genome surveillance data particularly in endemic (LMICs). An unknown number of mpox cases in LMICs are not
regions, little information about MPXV recombination is available (Yeh captured due to a shortage of resources like limited testing and
et al., 2022). However, there are some evidences of recombination surveillance capacity (Malta et al., 2022). As highlighted by Malta
between coinfecting or superinfecting OPXVs both in a laboratory et al., the MPXV vaccines are presently accessible only in high-income
setting and in nature (Estep et al., 2011; Goff et al., 2011; Brennan et al., countries (Canada, the USA, and the UK) (Malta et al., 2022).
2022; Diaz-Cánova et al., 2022b, 2022a; Gigante et al., 2022).
MPXV circulating in non-endemic regions where other OPXVs
are endemic, for instance, CPXV in Europe and VACV-like in south 8 Conclusion
America, and vaccination against mpox with JYNNEOUS or ACAM
2000 are scenarios for coinfection and superinfection between MPXV has emerged and re-emerged for over five decades and yet
different species of OPXV. Thus, there remains a potential risk of not much is known about its virological profile and the characteristics
recombination between MPXV and other OPXVs that may result in of the disease it causes. In particular, the reservoir host of MPXV
MPXVs with mosaic genomes and altered biological characteristics. remains unknown, the viral, host and environmental factors that
modulate the virus maintenance in the wild, animal-to-animal
transmission, zoonotic transmission and reverse spillover are still a
7.2 Dual use and bioterrorism mystery. Neither are we closer to reliable prognostication of virus
emergence and accurate modelling of the disease outcomes. Current
Although there is insufficient evidence of MPXV being used for and future studies should prioritize understanding the molecular basis
bioterrorism at the moment (Hosseini-Shokouh et al., 2022), many of MPXV infection to develop effective drugs and vaccines against
scientists have expressed concerns over its potential use for mpox as well as functional mutational studies that will shed insight into
bioterrorism because there is a report that there was an attempt the dynamics of MPXV transmission across hosts. To improve tracking
by the former Soviet Union to use MPXV as a bioweapon (Nalca of MPXV, laboratories particularly in resource-poor countries should
et al., 2005; Duraffour et al., 2007; Kindrachuk et al., 2012; Hosseini- be equipped with genome-based surveillance capacity and capability.
Shokouh et al., 2022; Makkar, 2022). The possibility of MPXV as a Lastly, MPXV and mpox affect human, animal, and ecosystem health.
potential bioweapon due to its global reemergence and its clinical Thus, a One Health strategy is indispensable to the prevention and
similarities with VARV has placed the virus on the global public treatment of current and future outbreaks.
health agenda (Ellis et al., 2012; Ihekweazu et al., 2020). For
example, the USA has made preparation for the possibility of
smallpox virus as a potential bioterror biological by storing Author contributions
smallpox vaccines and antivirals after the 9/11 attack (Franz,
2004; Xiang and White, 2022). Smallpox virus is in category A of MO: Conceptualization, Data curation, Investigation,
the CDC list of bioterrorism agents (Hosseini-Shokouh et al., 2022). Methodology, Supervision, Writing – original draft, Writing –
The risk of bioterrorism is heightened knowing that MPXV review & editing. EA: Formal analysis, Investigation,
genomes can be synthesized from publicly available sequence data Methodology, Writing – original draft, Writing – review &
and life viruses (with or without further genetic modification) can editing. DK: Formal analysis, Methodology, Writing – original
be re-constituted. This has already been demonstrated with draft. DD: Data curation, Formal analysis, Investigation, Writing
horsepox virus (HPXV), which shares the same genus as MPXV – original draft. FA: Investigation, Writing – original draft. OA:
(Noyce et al., 2018). Hence, a strict dual-use policy must be agreed Formal analysis, Investigation, Writing – original draft. UM:
upon and implemented in all laboratories across the globe. Conceptualization, Investigation, Methodology, Writing – original
draft, Writing – review & editing.

7.3 Stigmatization and vaccine inequity

Funding
Sexual orientation (especially LGBQTI+ community) (Sousa et al.,
2022) and racial (Happi et al., 2022) are two stigmas associated with The author(s) declare financial support was received for the
MPXV. The persistent narrative of the media alongside many scientists research, authorship, and/or publication of this article. The APC

Frontiers in Cellular and Infection Microbiology 15 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

was covered by funds from The University of Tromsø—The Arctic Publisher’s note
University of Norway.
All claims expressed in this article are solely those of the authors
Conflict of interest and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
The authors declare that the research was conducted in the reviewers. Any product that may be evaluated in this article, or
absence of any commercial or financial relationships that could be claim that may be made by its manufacturer, is not guaranteed or
construed as a potential conflict of interest. endorsed by the publisher.

References
Adegboye, O. A., Castellanos, M. E., Alele, F. O., Pak, A., Ezechukwu, H. C., Hou, K., Bahar, M. W., Kenyon, J. C., Putz, M. M., Abrescia, N. G. A., Pease, J. E., Wise, E. L.,
et al. (2022). Travel-related monkeypox outbreaks in the era of COVID-19 pandemic: et al. (2008). Structure and function of A41, a vaccinia virus chemokine binding
are we prepared? Viruses 14, 1–7. doi: 10.3390/v14061283 protein. PLoS Pathog. 4, 0055–0068. doi: 10.1371/journal.ppat.0040005
Aden, T.A., Blevins, P., York, S.W., Rager, S., Balachandran, D., Huston, C.L., et al Barry, M., Hnatiuk, S., Mossman, K., Lee, S. F., Boshkov, L., and McFadden, G.
(2022). Rapid diagnostic testing for response to the monkeypox outbreak — Laboratory (1997). The myxoma virus M-T4 gene encodes a novel RDEL-containing protein that is
response network, United States, may 17–june 30, 2022. MMWR Morb. Mortal Wkly. retained within the endoplasmic reticulum and is important for the productive
Rep. 71, 904–907. doi: 10.15585/mmwr.mm7128e1 infection of lymphocytes. Virology 239, 360–377. doi: 10.1006/viro.1997.8894
Agrati, C., Cossarizza, A., Mazzotta, V., Grassi, G., Casetti, R., Biasi, S., et al. (2022). Bass, J., Tack, D. M., McCollum, A. M., Kabamba, J., Pakuta, E., Malekani, J., et al.
Immunological signature in human cases of monkeypox infection in 2022 outbreak: (2013). Enhancing health care worker ability to detect and care for patients with
an observational study. Lancet Infect. Dis. 23, 320–330. doi: 0.1016/S1473-3099(22)00662-4 monkeypox in the democratic republic of the Congo. Int. Health 5, 237–243.
Alakunle, E., Moens, U., Nchinda, G., and Okeke, M. I. (2020). Monkeypox virus in doi: 10.1093/inthealth/iht029
Nigeria: infection biology, epidemiology, and evolution. Viruses 12, 1–29. doi: 10.3390/ Beer, E. M., and Bhargavi Rao, V. (2019). A systematic review of the epidemiology of
v12111257 human monkeypox outbreaks and implications for outbreak strategy. PloS Negl. Trop.
Alakunle, E. F., and Okeke, M. I. (2022). Monkeypox virus : a neglected zoonotic Dis. 13, 1–20. doi: 10.1371/journal.pntd.0007791
pathogen spreads globally. Nat. Rev. Microbiol. 20, 507–508. doi: 10.1038/s41579-022- Beerli, C., Yakimovich, A., Kilcher, S., Reynoso, G. V., Fläschner, G., Müller, D. J., et al.
00776-z (2019). Vaccinia virus hijacks EGFR signalling to enhance virus spread through rapid and
Alcami, A., and Smith, G. L. (1992). A soluble receptor for interleukin-1b encoded by directed infected cell motility. Nat. Microbiol. 4, 216–225. doi: 10.1038/s41564-018-0288-2
vaccinia virus: A novel mechanism of virus modulation of the host response to Benfield, C. T. O., Ren, H., Lucas, S. J., Bahsoun, B., and Smith, G. L. (2013). Vaccinia
infection. Cell 71, 153–167. doi: 10.1016/0092-8674(92)90274-G virus protein K7 is a virulence factor that alters the acute immune response to infection.
Alcamı́, A., and Smith, G. L. (1995). Vaccinia, cowpox, and camelpox viruses encode J. Gen. Virol. 94, 1647–1657. doi: 10.1099/vir.0.052670-0
soluble gamma interferon receptors with novel broad species specificity. J. Virol. 69, Besombes, C., Gonofio, E., Konamna, X., Selekon, B., Gessain, A., Berthet, N., et al.
4633–4639. doi: 10.1128/jvi.69.8.4633-4639.1995 (2019). Intrafamily transmission of monkeypox virus, Central African Republi. Emerg.
Alejo, A., Ruiz-Argüello, M. B., Ho, Y., Smith, V. P., Saraiva, M., and Alcami, A. Infect. Dis. 25, 1602–1604. doi: 10.3201/eid2508.190112
(2006). A chemokine-binding domain in the tumor necrosis factor receptor from Blasco, R., and Moss, B. (1992). Role of cell-associated enveloped vaccinia virus in cell-to-
variola (smallpox) virus. Proc. Natl. Acad. Sci. U. S. A. 103, 5995–6000. doi: 10.1073/ cell spread. Am. Soc Microbiol. 66, 4170–4179. doi: 10.1128/jvi.66.7.4170-4179.1992
pnas.0510462103 Born, T. L., Morrison, L. A., Esteban, D. J., VandenBos, T., Thebeau, L. G., Chen, N.,
Alkhalil, A., Hammamieh, R., Hardick, J., Ichou, M. A., Jett, M., and Ibrahim, S. et al. (2000). A poxvirus protein that binds to and inactivates IL-18, and inhibits NK cell
(2010). Gene expression profiling of monkeypox virus-infected cells reveals novel response. J. Immunol. 164, 3246–3254. doi: 10.4049/jimmunol.164.6.3246
interfaces for host-virus interactions. Virology 7, 1–19. doi: 10.1186/1743-422X-7-173 Bowie, A., Kiss-Toth, E., Symons, J. A., Smith, G. L., Dower, S. K., and O’Neill, L. A. J.
Al-musa, A., Chou, J., and Labere, B. (2022). The resurgence of a neglected (2000). A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor
orthopoxvirus: Immunologic and clinical aspects of monkeypox virus infections over signaling. Proc. Natl. Acad. Sci. U.S.A. 97, 10162–10167. doi: 10.1073/pnas.160027697
the past six decades. Clin. Immunol. 243, 109108. doi: 10.1016/j.clim.2022.109108 Bragazzi, N. L., Kong, J. D., Mahroum, N., Tsigalou, C., Khamisy-Farah, R., Converti,
Altindis, M., Puca, E., and Shapo, L. (2022). Diagnosis of monkeypox virus – An M., et al. (2023). Epidemiological trends and clinical features of the ongoing
overview. Travel Med. Infect. Dis. 50, 102459. doi: 10.1016/j.tmaid.2022.102459 monkeypox epidemic: A preliminary pooled data analysis and literature review. J.
Med. Virol. 95, e27931. doi: 10.1002/jmv.27931
Americo, J. L., Earl, P. L., and Moss, B. (2023). Virulence differences of mpox
(monkeypox) virus clades I, IIa, and IIb.1 in a small animal model. Proc. Natl. Acad. Sci. Branda, F., Pierini, M., and Mazzoli, S. (2023). Monkeypox: Early estimation of basic
U. S. A. 120, 4–9. doi: 10.1073/pnas.2220415120 reproduction number R0 in Europe. J. Med. Virol. 95, e28270. doi: 10.1002/jmv.28270
Anderson, M. G., Frenkel, L. D., Homann, S., and Guffey, J. (2003). A case of severe Breman, J. G., Nakano, J. H., Coffi, E., Godfrey, H., and Gautun, J. C. (1977). Human
monkeypox virus disease in an American child: Emerging infections and changing professional poxvirus disease after smallpox eradication. Am. J. Trop. Med. Hyg. 26, 273–281.
values. Pediatr. Infect. Dis. J. 22, 1093–1096. doi: 10.1097/01.inf.0000101821.61387.a5 doi: 10.4269/ajtmh.1977.26.273
Antinori, A., Mazzotta, V., Vita, S., Carletti, F., Tacconi, D., Lapini, L. E., et al. (2022). Breman, J. G., Ruti, K., and Steniowski, M. V. (1980). Human monkeypox 1970-79.
Epidemiological, clinical and virological characteristics of four cases of monkeypox Bull. World Health Organ. 58, 165–182.
support transmission through sexual contact, Italy, May 2022. Eurosurveillance 27, 1–6. Brennan, G., Stoian, A. M. M., Yu, H., Rahman, M. J., Banerjee, S., Stroup, J. N., et al.
doi: 10.2807/1560-7917.ES.2022.27.22.2200421 (2022). Molecular mechanisms of poxvirus evolution. Am. Soc Microbiol. 14, e0152622.
Aoyagi, M., Zhai, D., Jin, C., Aleshin, A. E., Stec, B., Reed, J. C., et al. (2006). Vaccinia doi: 10.1128/mbio.01526-22
virus N1L protein resembles a B cell lymphoma-2 (Bcl-2) family protein. Protein Sci. Brown, K., and Leggat, P. A. (2016). Human monkeypox: Current state of knowledge and
16, 118–124. doi: 10.1110/ps.062454707 implications for the future. Trop. Med. Infect. Dis. 1, 1–13. doi: 10.3390/tropicalmed1010008
Arita, I., and Henderson, D. A. (1968). Smallpox and monkeypox in non-human Buller, R. M. L., Chakrabarti, S., Moss, B., and Fredricksont, T. (1988). Cell
primates. Bull. World Health Organ. 39, 277–283. proliferative response to vaccinia virus is mediated by VGF. Virology 164, 182–192.
Arndt, W. D., Cotsmire, S., Trainor, K., Harrington, H., Hauns, K., Kibler, K. V., et al. doi: 10.1016/0042-6822(88)90635-6
(2015). Evasion of the innate immune type I interferon system by monkeypox virus. J. Bunge, E. M., Hoet, B., Chen, L., Lienert, F., Weidenthaler, H., Baer, L. R., et al.
Virol. 89, 10489–10499. doi: 10.1128/JVI.00304-15 (2022). The changing epidemiology of human monkeypox—A potential threat? A
Arndt, W. D., White, S. D., Johnson, B. P., Huynh, T., Liao, J., Harrington, H., et al. systematic review. PloS Negl. Trop. Dis. 16, 1–20. doi: 10.1371/journal.pntd.0010141
(2016). Monkeypox virus induces the synthesis of less dsRNA than vaccinia virus, and Campbell, J. A., Trossman, D. S., Yokoyama, W. M., and Carayannopoulos, L. N.
is more resistant to the anti-poxvirus drug, IBT, than vaccinia virus. Virology 497, 125– (2007). Zoonotic orthopoxviruses encode a high-affinity antagonist of NKG2D. J. Exp.
135. doi: 10.1016/j.virol.2016.07.016 Med. 204, 1311–1317. doi: 10.1084/jem.20062026
Arthur, R., Upadhayay, S., Arthur, R., Soni, D., Yadav, P., and Navik, U. (2022). Center for Diseases Control and Prevention (CDC). (2022a). Case Definitions† for
Monkeypox infection : The past , present , and future. Int. Immunopharmacol. 113, Use in the 2022 Mpox Response | Mpox | Poxvirus | CDC. (United States of America:
109382. doi: 10.1016/j.intimp.2022.109382

Frontiers in Cellular and Infection Microbiology 16 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

Center for Diseases Control and Prevention (CDC)). Available at: https://www.cdc.gov/ Eaglesham, J. B., Pan, Y., Kupper, T. S., and Kranzusch, P. J. (2019). Viral and
poxvirus/monkeypox/clinicians/case-definition.html (Accessed February 4, 2023). metazoan poxins are cGAMP-specific nucleases that restrict cGAS–STING signalling.
Center for Diseases Control and Prevention (CDC). (2022b). Severe Manifestations of Nature 566, 259–263. doi: 10.1038/s41586-019-0928-6
Monkeypox among People who are Immunocompromised Due to HIV or Other Conditions. Earl, P. L., Americo, J. L., and Moss, B. (2012). Lethal monkeypox virus infection of
Center for Diseases Control and Prevention (CDC). (2023). Past U.S. Cases and CAST/eiJ mice is associated with a deficient gamma interferon response. J. Virol. 86,
Outbreaks | Mpox | Poxvirus | CDC. (United States of America). Available at: https:// 9105–9112. doi: 10.1128/JVI.00162-12
www.cdc.gov/poxvirus/monkeypox/outbreak/us-outbreaks.html (Accessed February 2, El Eid, R., Allaw, F., Haddad, S. F., and Kanj, S. S. (2022). Human monkeypox: A
2023). review of the literature. PloS Pathog. 18, e1010768. doi: 10.1371/journal.ppat.1010768
Centre for Disease Control. (2003). Multistate Outbreak of Monkeypox— Illinois, Ellis, C. K., Carroll, D. S., Lash, R. R., Townsend Peterson, A., Damon, I. K.,
Indiana, and Wisconsi (United States of America: American Medical Association Malekani, J., et al. (2012). Ecology and geography of human monkeypox case
(AMA)). doi: 10.1001/jama.290.1.30 occurrences across Africa. J. Wildl. Dis. 48, 335–347. doi: 10.7589/0090-3558-48.2.335
Chandran, D., Dhama, K., K, M. A. M., Chakraborty, S., Mohapatra, R. K., Yatoo, M. Ember, S. W. J., Ren, H., Ferguson, B. J., and Smith, G. L. (2012). Vaccinia virus
I., et al. (2022). Monkeypox : an update on current knowledge and research advances. J. protein C4 inhibits NF-kB activation and promotes virus virulence. J. Gen. Virol. 93,
Exp. Biol. Agric. Sci. 10, 679–688. doi: 10.18006/2022.10(4) 2098–2108. doi: 10.1099/vir.0.045070-0
Cheema, A. Y., Ogedegbe, O. J., Munir, M., Alugba, G., and Ojo, T. K. (2022). Erez, N., Achdout, H., Milrot, E., Schwartz, Y., Wiener-Well, Y., Paran, N., et al.
Monkeypox : A review of clinical features , diagnosis , and treatment. Cureus 14, 14–17. (2019). Diagnosis of imported monkeypox, Israe. Emerg. Infect. Dis. 25, 980–983.
doi: 10.7759/cureus.26756 doi: 10.3201/eid2505.190076
Chen, N., Li, G., Liszewski, M. K., Atkinson, J. P., Jahrling, P. B., Feng, Z., et al. Estep, R. D., Messaoudi, I., O’Connor, M. A., Li, H., Sprague, J., Barron, A., et al.
(2005). Virulence differences between monkeypox virus isolates from West Africa and (2011). Deletion of the monkeypox virus inhibitor of complement enzymes locus
the Congo basin. Virology 340, 46–63. doi: 10.1016/j.virol.2005.05.030 impacts the adaptive immune response to monkeypox virus in a nonhuman primate
model of infection. J. Virol. 85, 9527–9542. doi: 10.1128/JVI.00199-11
Chen, R. A. J., Ryzhakov, G., Cooray, S., Randow, F., and Smith, G. L. (2008).
Inhibition of IkB kinase by vaccinia virus virulence factor B14. PLoS Pathog. 4, e22. Falendysz, E. A., Lopera, J. G., Rocke, T. E., and Osorio, J. E. (2023). Monkeypox
doi: 10.1371/journal.ppat.0040022 virus in animals: current knowledge of viral transmission and pathogenesis in wild
animal reservoirs and captive animal models. Viruses 15, 905. doi: 10.3390/v15040905
Colamonici, O. R., Domanski, P., Sweitzer, S. M., Larner, A., and Buller, R. M. L.
(1995). Vaccinia virus B18R gene encodes a type I interferon-binding protein that Fang, E. S. Y., Ng, O. T., Marc, J. Z. H., Mak, T. M., Marimuthu, K., Vasoo, S., et al.
blocks interferon a transmembrane signaling. J. Biol. Chem. 270, 15974–15978. (2020). Imported monkeypox, Singapore. Emerg. Infect. Dis. 26, 1826–1830.
doi: 10.1074/jbc.270.27.15974 doi: 10.3201/eid2608.191387
Cooray, S., Bahar, M. W., Abrescia, N. G. A., McVey, C. E., Bartlett, N. W., Chen, R. A. Faye, O., Pratt, C. B., Faye, M., Fall, G., Chitty, J. A., Diagne, M. M., et al. (2018).
J., et al. (2007). Functional and structural studies of the vaccinia virus virulence factor N1 Genomic characterisation of human monkeypox virus in Nigeria. Lancet Infect. Dis. 18,
reveal a Bcl-2-like anti-apoptotic protein. J. Gen. Virol. 88, 1656–1666. doi: 10.1099/ 246. doi: 10.1016/S1473-3099(18)30043-4
vir.0.82772-0 Ferná ndez de Marco, M., del, M., Alejo, A., Hudson, P., Damon, I. K., and Alcami, A.
Croft, D. R., Sotir, M. J., Williams, C. J., Kazmierczak, J. J., Wegner, M. V., Rausch, (2010). The highly virulent variola and monkeypox viruses express secreted inhibitors
D., et al. (2007). Occupational risks during a monkeypox outbreak, Wisconsi. Emerg. of type I interferon. FASEB J. 24, 1479–1488. doi: 10.1096/fj.09-144733
Infect. Dis. 13, 1150–1157. doi: 10.3201/eid1308.061365 Firth, C., Kitchen, A., Shapiro, B., Suchard, M. A., Holmes, E. C., and Rambaut, A.
Cuerel, A., Favre, G., Vouga, M., and Pomar, L. (2022). Monkeypox and pregnancy : (2010). Using time-structured data to estimate evolutionary rates of double-stranded
latest updates. Viruses 14, 1–12. doi: 10.3390/v14112520 DNA viruses. Mol. Biol. Evol. 27, 2038–2051. doi: 10.1093/molbev/msq088
Curran, K. G., Eberly, K., Russell, O. O., Snyder, R. E., Phillips, E. K., Tang, E. C., et al. Fischer, F., Mehrl, A., Kandulski, M., Schlosser, S., Müller, M., and Schmid, S. (2022).
(2022). HIV and sexually transmitted infections among persons with monkeypox — Monkeypox in a patient with controlled HIV infection initially presenting with fever , painful
Eight U.S. Jurisdictions, may 17–july 22, 2022. MMWR. Morb. Mortal. Wkly. Rep. 71, pharyngitis , and tonsillitis. Medicina (B. Aires). 58, 1–6. doi: 10.3390/medicina58101409
1141–1147. doi: 10.15585/mmwr.mm7136a1 Forni, D., Cagliani, R., Molteni, C., Clerici, M., and Sironi, M. (2022a). Monkeypox
Damon, I. K. (2011). Status of human monkeypox: Clinical disease, epidemiology virus: The changing facets of a zoonotic pathogen. Infect. Genet. Evol. 105, 105372.
and research. Vaccine 29, D54–D59. doi: 10.1016/j.vaccine.2011.04.014 doi: 10.1016/j.meegid.2022.105372
DeHaven, B. C., Girgis, N. M., Xiao, Y., Hudson, P. N., Olson, V. A., Damon, I. K., Forni, D., Molteni, C., Cagliani, R., and Sironi, M. (2022b). Geographic structuring
et al. (2010). Poxvirus complement control proteins are expressed on the cell surface and divergence time frame of monkeypox virus in the endemic region. J. Infect. Dis. 1,
through an intermolecular disulfide bridge with the viral A56 protein. J. Virol. 84, 1–10. doi: 10.1093/infdis/jiac298
11245–11254. doi: 10.1128/JVI.00372-10 Franz, M. (2004). Development and Characterization of Monoclonal Antibodies Directed
Deng, L., Dai, P., Parikh, T., Cao, H., Bhoj, V., Sun, Q., et al. (2008). Vaccinia virus Against Tanapox Virus. (Kalamazoo, Michigan: Western Michigan University).
subverts a mitochondrial antiviral signaling protein-dependent innate immune Frenois-Veyrat, G., Gallardo, F., Gorgé, O., Marcheteau, E., Ferraris, O., Baidaliuk, A., et al.
response in keratinocytes through its double-stranded RNA binding protein, E3. J. (2022). Tecovirimat is effective against human monkeypox virus in vitro at nanomolar
Virol. 82, 10735–10746. doi: 10.1128/JVI.01305-08 concentrations. Nat. Microbiol. 7, 1951–1955. doi: 10.1038/s41564-022-01269-8
Denhardt, D. T. (1996). Signal-transducing protein phosphorylation cascades Gessain, A., Nakoune, E., and Yazdanpanah, Y. (2022). Monkeypox. N. Engl. J. Med.
mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex 19, 1–11. doi: 10.1056/NEJMra2208860
signalling. Biochem. J. 318, 729–747. doi: 10.1042/bj3180729
Ghaffar, R. A., and Shahnoor, S. (2022). Increased prevalence of HIV among
Dewitt, M. E., Polk, C., Williamson, J., Shetty, A. K., Passaretti, C. L., and Mcneil, C. J. Monkeypox patients – An alarming update. New Microbes New Infect. 49–50,
(2022). Global monkeypox case hospitalisation rates : A rapid systematic review and 101039. doi: 10.1016/j.nmni.2022.101039
meta-analysis. eClinicalMedicine 54, 101710. doi: 10.1016/j.eclinm.2022.101710
Gigante, C. M., Korber, B., Seabolt, M. H., Wilkins, K., Davidson, W., Rao, A. K., et al.
Diaz-Cá nova, D., Mavian, C., Brinkmann, A., Nitsche, A., Moens, U., and Okeke, M. (2022). Multiple lineages of monkeypox virus detected in the United States 2021–2022.
I. (2022a). Genomic sequencing and phylogenomics of cowpox virus. Viruses 14, 1–16. Science 378, 560–565. doi: 10.1126/science.add4153
doi: 10.3390/v14102134
Gileva, I. P., Nepomnyashchikh, T. S., Antonets, D. V., Lebedev, L. R., Kochneva, G.
Diaz-Cá nova, D., Moens, U. L., Brinkmann, A., Nitsche, A., and Okeke, M. I. V., Grazhdantseva, A. V., et al. (2006). Properties of the recombinant TNF-binding
(2022b). Genomic sequencing and analysis of a novel human cowpox virus with mosaic proteins from variola, monkeypox, and cowpox viruses are different. Biochim. Biophys.
sequences from North America and old world orthopoxvirus. Front. Microbiol. 13. Acta - Proteins Proteomics 1764, 1710–1718. doi: 10.1016/j.bbapap.2006.09.006
doi: 10.3389/fmicb.2022.868887
Girgis, N. M., DeHaven, B. C., Xiao, Y., Alexander, E., Viner, K. M., and Isaacs, S. N.
Dinarello, C. A. (2018). Overview of the IL-1 family in innate inflammation and (2011). The vaccinia virus complement control protein modulates adaptive immune
acquired immunity. Immunol. Rev. 281, 8–27. doi: 10.1111/imr.12621 responses during infection. J. Virol. 85, 2547–2556. doi: 10.1128/JVI.01474-10
Domán, M., Fehér, E., Varga-Kugler, R., Jakab, F., and Bányai, K. (2022). Animal models Giulio, D.B.D., and Eckburg, P. B. (2004). Human monkeypox: an emerging
used in monkeypox research. Microorganisms 10 2192. doi: 10.3390/microorganisms10112192 zoonosis. Lancet Infect. Dis. 4, 15–25. doi: 10.1016/s1473-3099(03)00856-9
Dumonteil, E., Herrera, C., and Sabino-Santos, G. (2023). Monkeypox virus evolution Goff, A., Mucker, E., Raymond, J., Fisher, R., Bray, M., Hensley, L., et al. (2011).
before 2022 outbreak. Emerg. Infect. Dis. 29, 451–453. doi: 10.3201/eid2902.220962 Infection of cynomolgus macaques with a recombinant monkeypox virus encoding green
Duraffour, S., Ishchenko, A. A., Saparbaev, M., Crance, J. M., and Garin, D. (2007). fluorescent protein. Arch. Virol. 156, 1877–1881. doi: 10.1007/s00705-011-1065-1
Substrate specificity of homogeneous monkeypox virus uracil-DNA glycosylase. Goyal, L., Ajmera, K., Pandit, R., and Pandit, T. (2022). Prevention and treatment of
Biochemistry 46, 11874–11881. doi: 10.1021/bi700726a monkeypox: A step-by-step guide for healthcare professionals and general population.
Durski, K. N., McCollum, A. M., Nakazawa, Y., Petersen, B. W., Reynolds, M. G., Cureus 14, 1–13. doi: 10.7759/cureus.28230
Briand, S., et al. (2018). Emergence of monkeypox — West and Central Africa 1970– Greber, U. F. (2002). Signalling in viral entry. Cell. Mol. Life Sci. 58, I. doi: 10.1007/
2017. Morb. Mortal. Wkly. Rep. 67, 306-310. doi: 10.15585/mmwr.mm6710a5 s00018-002-8453-3

Frontiers in Cellular and Infection Microbiology 17 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

Grothe, J. H., Cornely, O. A., and Salmanton-Garcı́a, J. (2022). Monkeypox Khalili, A., Samara, A., O’Brien, P., Coutinho, C. M., Duarte, G., Quintana, S. M.,
diagnostic and treatment capacity at epidemic onset: A VACCELERATE online et al. (2020). Monkeypox in pregnancy: update on current outbreak. Lancet 22, 2020–
survey. J. Infect. Public Health 15, 1043–1046. doi: 10.1016/j.jiph.2022.08.008 2022. doi: 10.1016/s1473-3099(03)00856-9
Gruber, M. F. (2022). Current status of monkeypox vaccines. NPJ Vaccines 7, 1–3. Kindrachuk, J., Arsenault, R., Kusalik, A., Kindrachuk, K. N., Trost, B., Napper, S.,
doi: 10.1038/s41541-022-00527-4 et al. (2012). Systems kinomics demonstrates congo basin monkeypox virus infection
Hammarlund, E., Dasgupta, A., Pinilla, C., Norori, P., Früh, K., and Slifka, M. K. selectively modulates host cell signaling responses as compared to West African
(2008). Monkeypox virus evades antiviral CD4+ and CD8+ T cell responses by monkeypox virus. Mol. Cell. Proteomics 11, 1–12. doi: 10.1074/mcp.M111.015701
suppressing cognate T cell activation. Proc. Natl. Acad. Sci. U.S.A. 105, 14567–14572. Kipkorir, V., Dhali, A., Srichawla, B., Kutikuppala, S., Cox, M., Ochieng, D., et al. (2022). The
doi: 10.1073/pnas.0800589105 re-emerging monkeypox disease. Trop. Med. Int. Heal. 27, 961–969. doi: 10.1111/tmi.13821
Happi, C., Adetifa, I., Mbala, P., Njouom, R., Nakoune, E., Happi, A., et al. (2022). Kmiec, D., and Kirchhoff, F. (2022). Monkeypox: A new threat? Int. J. Mol. Sci. 23,
Urgent need for a non-discriminatory and non-stigmatizing nomenclature for 7866. doi: 10.3390/ijms23147866
monkeypox virus. PLoS Biol. 20, 1–6. doi: 10.1371/journal.pbio.3001769 Kotwal, G. J., Isaacs, S. N., Mckenzie, R., Frank, M. M., and Moss, B. (1990).
Harapan, H., Ophinni, Y., Megawati, D., Frediansyah, A., and Mamada, S. S. (2022). Inhibition of the complement cascade by the major secretory protein of vaccinia virus.
Monkeypox : A comprehensive review. Viruses 14, 1–26. doi: 10.3390/v14102155 Science 250, 827–830. doi: 10.1126/science.2237434
Harris, R. S., and Dudley, J. P. (2015). APOBECs and virus restriction. Virology 479– Krajcsi, P., and Wold, W. S. M. (1998). Viral proteins that regulate cellular signalling.
480, 131-145. doi: 10.1016/j.virol.2015.03.012 J. Gen. Virol. 79, 1323–1335. doi: 10.1099/0022-1317-79-6-1323
Harrison, D.A (1990). The JAK/STAT pathway: fact sheet. Cold Spring Harb. Kugelman, J. R., Johnston, S. C., Mulembakani, P. M., Kisalu, N., Lee, M. S., Koroleva,
Perspect. Biol. 4, a011205. G., et al. (2014). Genomic variability of monkeypox virus among humans , democratic
Harte, M. T., Haga, I. R., Maloney, G., Gray, P., Reading, P. C., Bartlett, N. W., et al. republic of the congo. Emerg. Infect. Dis. 20, 2–9. doi: 10.3201/eid2002.130118
(2003). The poxvirus protein A52R targets toll-like receptor signaling complexes to Kumar, R., Nagar, S., Haider, S., Sood, U., Ponnusamy, K., and Dhingra, G. G. (2023).
suppress host defense. J. Exp. Med. 197, 343–351. doi: 10.1084/jem.20021652 Monkeypox virus: phylogenomics , host – pathogen interactome and mutational
Hayden, M. S., and Ghosh, S. (2008). Shared principles in NF-kB signaling. Cell 132, cascade. Microb Genom. 9, mgen00987. doi: 10.1099/mgen.0.000987
344–362. doi: 10.1016/j.cell.2008.01.020 Ladnyj, I. D., Ziegler, P., and Kima, E. (1972). A human infection caused by
Hendrickson, R. C., Wang, C., Hatcher, E. L., and Lefkowitz, E. J. (2010). Orthopoxvirus monkeypox virus in Basankusu Territory, Democratic Republic of the Congo. Bull.
genome evolution: The role of gene loss. Viruses 2, 1933–1967. doi: 10.3390/v2091933 World Health Organ. 46, 593–597.

Herbert, M. H., Squire, C. J., and Mercer, A. A. (2015). Poxviral ankyrin proteins. Lazear, E., Peterson, L. W., Nelson, C. A., and Fremont, D. H. (2013). Crystal
Viruses 7, 709–738. doi: 10.3390/v7020709 structure of the cowpox virus-encoded NKG2D ligand OMCP. J. Virol. 87, 840–850.
doi: 10.1128/JVI.01948-12
Heymann, D. L., Szczeniowski, M., and Esteves, K. (1998). Re-emergence of
monkeypox in Africa: A review of the past six years. Br. Med. Bull. 54, 693–702. Leung, J., Mccollum, A. M., Radford, K., Hughes, C., Lopez, A.S., Guagliardo, S.A.J.,
doi: 10.1093/oxfordjournals.bmb.a011720 et al. (2019). Varicella in tshuapa province , Democratic Republic of Congo, 2009 –
2014. Trop. Med. Int. Heal. 24, 839–848. doi: 10.1111/tmi.13243
Hnatiuk, S., Barry, M., Zeng, W., Liu, L., Lucas, A., Percy, D., et al. (1999). Role of the
C-terminal RDEL motif of the myxoma virus M-T4 protein in terms of apoptosis Li, M., and Beg, A. A. (2000). Induction of necrotic-like cell death by tumor necrosis
regulation and viral pathogenesis. Virology 263, 290–306. doi: 10.1006/viro.1999.9946 factor alpha and caspase inhibitors: novel mechanism for killing virus-infected cells. J.
Virol. 74, 7470–7477. doi: 10.1128/JVI.74.16.7470-7477.2000
Hobson, G., Adamson, J., Adler, H., Firth, R., Gould, S., Houlihan, C., et al. (2021).
Family cluster of three cases of monkeypox imported from Nigeria to the United Li, K., Yuan, Y., Jiang, L., Liu, Y., Liu, Y., and Zhang, L. (2023). Animal host range of
K i n g d o m , M a y 2 0 2 1 . E u ro s u r v e i l l a n c e 2 6 , 1 – 4 . d o i : 1 0 . 2 8 0 7 / 1 5 6 0 - mpox virus. J. Med. Virol. 95, e28513. doi: 10.1002/jmv.28513
7917.ES.2021.26.32.2100745 Li, H., Zhang, H., Ding, K., Wang, X., Sun, G., and Liu, Z. (2022). The evolving
Hoff, N. A., Morier, D. S., Kisalu, N. K., Johnston, S. C., Doshi, R. H., Hensley, L. E., epidemiology of monkeypox virus. Cytokine Growth Factor Rev. 68, 1–12. doi: 10.1016/
et al. (2017). Varicella coinfection in patients with active monkeypox in the democratic j.cytogfr.2022.10.002
republic of the congo. Ecohealth 14, 564–574. doi: 10.1007/s10393-017-1266-5 Li, Y., Zhao, H., Wilkins, K., Hughes, C., and Damon, I. K. (2010). Real-time PCR
Hosseini-Shokouh, S.-J., Gholami, M., Barati, M., and Naghoosi, H. (2022). assays for the specific detection of monkeypox virus West African and Congo Basin
Monkeypox : A re-emerging viral zoonotic infection. Ann. Mil. Heal. Sci. Res. 20, strain DNA. J. Virol. Methods 169, 223–227. doi: 10.1016/j.jviromet.2010.07.012
e129475. doi: 10.5812/amh Likos, A. M., Sammons, S. A., Olson, V. A., Frace, A. M., Li, Y., Olsen-Rasmussen,
M., et al. (2005). A tale of two clades: Monkeypox viruses. J. Gen. Virol. 86, 2661–2672.
Hudson, P. N., Self, J., Weiss, S., Braden, Z., Xiao, Y., Girgis, N. M., et al. (2012).
doi: 10.1099/vir.0.81215-0
Elucidating the role of the complement control protein in monkeypox pathogenicity.
PloS One 7, e35086. doi: 10.1371/journal.pone.0035086 Liszewski, M. K., Leung, M. K., Hauhart, R., Buller, R. M. L., Bertram, P., Wang, X.,
et al. (2006). Structure and regulatory profile of the monkeypox inhibitor of
Hughes, C. M., Liu, L., Davidson, W. B., Radford, K. W., Wilkins, K., Monroe, B., complement: comparison to homologs in vaccinia and variola and evidence for
et al. (2021). A tale of two viruses : coinfections of monkeypox and varicella zoster virus dimer formation. J. Immunol. 176, 3725–3734. doi: 10.4049/jimmunol.176.6.3725
in the Democratic Republic of Congo. Am. J. Trop. Med. Hyg. 104, 604–611.
doi: 10.4269/ajtmh.20-0589 Liu, Q., Fu, L., Wang, B., Sun, Y., Wu, X., Peng, X., et al. (2023). Clinical
characteristics of human mpox (Monkeypox) in 2022: A systematic review and
Hutson, C. L., Carroll, D. S., Self, J., Weiss, S., Hughes, C. M., Braden, Z., et al. (2010). meta-analysis. Pathogens 12, 146. doi: 10.3390/pathogens12010146
Dosage comparison of Congo Basin and West African strains of monkeypox virus
using a prairie dog animal model of systemic orthopoxvirus disease. Virology 402, 72– Liu, R., and Moss, B. (2018). Vaccinia virus C9 ankyrin repeat/F-box protein is a
82. doi: 10.1016/j.virol.2010.03.012 newly identified antagonist of the type I interferon-induced antiviral state. J. Virol. 92,
1–17. doi: 10.1128/JVI.00053-18
Hutson, C. L., Olson, V. A., Carroll, D. D., Abel, J. A., Hughes, C. M., Braden, Z. H.,
et al. (2009). A prairie dog animal model of systemic orthopoxvirus disease using west Liu, J., Mucker, E. M., Chapman, J. L., Babka, A. M., Gordon, J. M., Bryan, A. V., et al.
African and Congo Basin strains of Monkeypox virus. J. Gen. Virol. 90, 323–333. (2022). Retrospective detection of monkeypox virus in the testes of nonhuman primate
doi: 10.1099/vir.0.005108-0 survivors. Nat. Microbiol 7, 1980-1986. doi: 10.1038/s41564-022-01259-w
Ihekweazu, C., Yinka-Ogunleye, A., Lule, S., and Ibrahim, A. (2020). Importance of Lourie, B., Bingham, P. G., Evans, H. H., Foster, S. O., Nakano, J. H., and Herrmann,
epidemiological research of monkeypox: is incidence increasing? Expert Rev. Anti K. L. (1972). Human infection with monkeypox virus: laboratory investigation of six
Infect. Ther. 18, 389–392. doi: 10.1080/14787210.2020.1735361 cases in West Africa. Bull. World Health Organ. 46, 633–639.
Isaacs, S. N., Kotwal, G. J., and Moss, B. (1992). Vaccinia virus complement-control Lum, F. M., Torres-Ruesta, A., Tay, M. Z., Lin, R. T. P., Lye, D. C., Ré nia, L., et al.
protein prevents antibody-dependent complement-enhanced neutralization of (2022). Monkeypox: disease epidemiology, host immunity and clinical interventions.
infectivity and contributes to virulence. Proc. Natl. Acad. Sci. U.S.A. 89, 628–632. Nat. Rev. Immunol. 22, 597–613. doi: 10.1038/s41577-022-00775-4
doi: 10.1073/pnas.89.2.628 Luna, N., Ramı́rez, A. L., Muñoz, M., Ballesteros, N., Patiño, L. H., Castañeda, S. A.,
Isidro, J., Borges, V., Pinto, M., Sobral, D., Santos, J. D., Nunes, A., et al. (2022). et al. (2022). Phylogenomic analysis of the monkeypox virus (MPXV) 2022 outbreak:
Phylogenomic characterization and signs of microevolution in the 2022 multi-country Emergence of a novel viral lineage? Travel Med. Infect. Dis. 49, 102402. doi: 10.1016/
outbreak of monkeypox virus. Nat. Med. 28, 1569–1572. doi: 10.1038/s41591-022-01907-y j.tmaid.2022.102402
Johnston, S. C., Johnson, J. C., Stonier, S. W., Lin, K. L., Kisalu, N. K., Hensley, L. E., Luo, Q., and Han, J. (2022). Preparedness for a monkeypox outbreak. Infect. Med. 1,
et al. (2015). Cytokine modulation correlates with severity of monkeypox disease in 124–134. doi: 10.1016/j.imj.2022.07.001
humans. J. Clin. Virol. 63, 42–45. doi: 10.1016/j.jcv.2014.12.001 Lysakova-Devine, T., Keogh, B., Harrington, B., Nagpal, K., Halle, A., Golenbock, D.
Kabuga, A. I., and El Zowalaty, M. E. (2019). A review of the monkeypox virus and a T., et al. (2010). Viral inhibitory peptide of TLR4, a peptide derived from vaccinia
recent outbreak of skin rash disease in Nigeria. J. Med. Virol. 91, 533–540. doi: 10.1002/ protein A46, specifically inhibits TLR4 by directly targeting myD88 adaptor-like and
jmv.25348 TRIF-related adaptor molecule. J. Immunol. 185, 4261–4271. doi: 10.4049/
jimmunol.1002013
Kalyar, F., Chen, X., Kunasekaran, M., Moa, A., Chughtai, A., and Maclntyre, R.
(2022). An unprecedented global resurgence of monkeypox. (Kalamazoo, Michigan: Makkar, D. (2022). The latest news for may 2022 all you need to know on monkeypox. IP
Global Biosecurity). doi: 10.31646/gbio.170 Int. J. Med. Microbiol. Trop. Dis. 8 (3), 183–195. doi: 10.18231/j.ijmmtd.2022.039

Frontiers in Cellular and Infection Microbiology 18 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

Malta, M., Mbala-Kingebeni, P., Rimoin, A. W., and Strathdee, S. A. (2022). Parker, S., and Buller, R. M. (2013). A review of experimental and natural infections
Monkeypox and global health inequities: A tale as old as time. Int. J. Environ. Res. of animals with monkeypox virus between 1958 and 2012. Future Virol. 8, 129–157.
Public Health 19, 10–13. doi: 10.3390/ijerph192013380 doi: 10.2217/fvl.12.130
Mann, B. A., Huang, J. H., Li, P., Chang, H. C., Slee, R. B., O’Sullivan, A., et al. (2008). Payne, L. G. (1980). Significance of extracellular enveloped virus in the in vitro and in
Vaccinia virus blocks Stat1-dependent and Stat1-independent gene expression induced by vivo dissemination of vaccinia. J. Gen. Virol. 50, 89–100. doi: 10.1099/0022-1317-50-1-89
type I and type II interferons. J. Interf. Cytokine Res. 28, 367–379. doi: 10.1089/jir.2007.0113 Pears, C. (1995). Structure and function of the protein kinase C gene family. J. Biosci.
Mansur, D. S., Maluquer de Motes, C., Unterholzner, L., Sumner, R. P., Ferguson, B. 20, 311–332. doi: 10.1007/BF02703836
J., Ren, H., et al. (2013). Poxvirus targeting of E3 ligase b-trCP by molecular mimicry: A Petersen, E., Kantele, A., Koopmans, M., Asogun, D., Ogunlete, A., Ihekweazu, C.,
mechanism to inhibit NF-kB activation and promote immune evasion and virulence. et al. (2019a). Human monkeypox –epidemiological and clinical characteristics,
PloS Pathog. 9, e1003183. doi: 10.1371/journal.ppat.1003183 diagnosis and prevention. Infect. Dis. Clin. 33, 1027–1043. doi: 10.1016/
Martin, D. P., Murrell, B., Golden, M., Khoosal, A., and Muhire, B. (2015). RDP4: j.idc.2019.03.001
Detection and analysis of recombination patterns in virus genomes. Virus Evol. 1, Petersen, E., Kantele, A., Koopmans, M., Asogun, D., Yinka-Ogunleye, A.,
vev003. doi: 10.1093/ve/vev003 Ihekweazu, C., et al. (2019b). Human monkeypox: epidemiologic and clinical
Mauldin, M. R., McCollum, A. M., Nakazawa, Y. J., Mandra, A., Whitehouse, E. R., characteristics, diagnosis, and prevention. Infect. Dis. Clin. North Am. 33, 1027–
Davidson, W., et al. (2022). Exportation of monkeypox virus from the african 1043. doi: 10.1016/j.idc.2019.03.001
continent. J. Infect. Dis. 225, 1367–1376. doi: 10.1093/infdis/jiaa559 Petersen, E., Zumla, A., Hui, D. S., Blumberg, L., Valdoleiros, S. R., Amao, L., et al.
Mbala, P. K., Huggins, J. W., Riu-Rovira, T., Ahuka, S. M., Mulembakani, P., Rimoin, (2022). Vaccination for monkeypox prevention in persons with high-risk sexual
A. W., et al. (2017). Maternal and fetal outcomes among pregnant women with human behaviours to control on-going outbreak of monkeypox virus clade 3. Int. J. Infect.
monkeypox infection in the Democratic Republic of Congo. J. Infect. Dis. 216, 824–828. Dis. 122, 569–571. doi: 10.1016/j.ijid.2022.06.047
doi: 10.1093/infdis/jix260 Phylogenetic pitchforks - Understanding Evolution. (2023). Available at: https://
McCarthy, M. W. (2022). Recent advances in the diagnosis monkeypox: implications for evolution.berkeley.edu/phylogenetic-systematics/reading-trees-a-quick-review/
public health. Expert Rev. Mol. Diagn. 22, 739–744. doi: 10.1080/14737159.2022.2116979 phylogenetic-pitchforks/ (Accessed February 3, 2023).
McCollum, A., Nakazawa, Y., Ndongala, G. M., Pukuta, E., Karhemere, S., Lushima, R. Poland, G. A., Kennedy, R. B., and Tosh, P. K. (2022). Prevention of monkeypox with
S., et al. (2014). Human monkeypox in the Kivus, a conflict region of The Democratic vaccines: a rapid review. Lancet Infect. Dis. 3099, 1–10. doi: 10.1016/S1473-3099(22)00574-6
Republic of the Congo. Int. J. Infect. Dis. 21, 192. doi: 10.1016/j.ijid.2014.03.820
Pourriyahi, H., Aryanian, Z., Afshar, Z. M., and Goodarzi, A. (2023). A systematic
Merouze, F., and Lesoin, J. J. (1983). [Monkeypox: second human case observed in review and clinical atlas on mucocutaneous presentations of the current monkeypox
Ivory Coast (rural health sector of Daloa]. Med. Trop. 43, 145–147. outbreak: With a comprehensive approach to all dermatologic and nondermatologic
Mitjà, O., Ogoina, D., Titanji, B. K., Galvan, C., Muyembe, J.-J., Marks, M., et al. aspects of the new and previous monkeypox outbreaks. J. Med. Virol. 95, e28230.
(2022). Monkeypox. Lancet. 401, 60–74. doi: 10.1016/S0140-6736(22)02075-X doi: 10.1002/jmv.28230
Mogensen, T. H. (2009). Pathogen recognition and inflammatory signaling in innate Rambaut, A., Drummond, A. J., Xie, D., Baele, G., and Suchard, M. A. (2018).
immune defenses. Clin. Microbiol. Rev. 22, 240–273. doi: 10.1128/CMR.00046-08 Posterior summarization in Bayesian phylogenetics using Tracer 1.7. Syst. Biol. 67, 901–
904. doi: 10.1093/sysbio/syy032
Mohamed, M. R., and McFadden, G. (2009). NFkB inhibitors: Strategies from
poxviruses. Cell Cycle 8, 3125–3132. doi: 10.4161/cc.8.19.9683 Rambaut, A., Lam, T. T., Carvalho, L. M., and Pybus, O. G. (2016). Exploring the
temporal structure of heterochronous sequences using TempEst (formerly Path-O-
Motwani, M., Pesiridis, S., and Fitzgerald, K. A. (2019). DNA sensing by the cGAS–
Gen). Virus Evol. 2, 1–7. doi: 10.1093/ve/vew007
STING pathway in health and disease. Nat. Rev. Genet. 20, 657–674. doi: 10.1038/
s41576-019-0151-1 Randall, R. E., and Goodbourn, S. (2008). Interferons and viruses: An interplay
between induction, signalling, antiviral responses and virus countermeasures. J. Gen.
Moulton, E. A., Atkinson, J. P., and Buller, R. M. L. (2008). Surviving mousepox
Virol. 89, 1–47. doi: 10.1099/vir.0.83391-0
infection requires the complement system. PLoS Pathog. 4, e1000249. doi: 10.1371/
journal.ppat.1000249 Realegeno, S., Priyamvada, L., Kumar, A., Blackburn, J. B., Hartloge, C., Puschnik, A.
S., et al. (2020). Conserved oligomeric golgi (COG) complex proteins facilitate
Nakazawa, Y., Emerson, G. L., Carroll, D. S., Zhao, H., Li, Y., Reynolds, M. G., et al.
orthopoxvirus entry, fusion and spread. Viruses 12, 707. doi: 10.3390/v12070707
(2013). Phylogenetic and ecologic perspectives of a monkeypox outbreak, Southern
Suda. Emerg. Infect. Dis. 19, 237–245. doi: 10.3201/eid1902.121220 Rehm, K. E., Connor, R. F., Jones, G. J. B., Yimbu, K., and Roper, R. L. (2011).
Vaccinia virus A35R inhibits MHC class II antigen presentation. Virology 23, 1–7.
Nakhaie, M., Arefinia, N., Charostad, J., Bashash, D., Haji Abdolvahab, M., and Zarei, doi: 10.1016/j.virol.2009.11.008.Vaccinia
M. (2022). Monkeypox virus diagnosis and laboratory testing. Rev. Med. Virol. 33, e204.
doi: 10.1002/rmv.2404 Reynolds, M. G., Davidson, W. B., Curns, A. T., Conover, C. S., Huhn, G., Davis, J. P.,
et al. (2007). Spectrum of infection and risk factors for human monkeypox, United
Nalca, A., Rimoin, A. W., Bavari, S., and Whitehouse, C. A. (2005). Reemergence of State. Emerg. Infect. Dis. 13, 1332–1339. doi: 10.3201/eid1309.070175
monkeypox : prevalence , diagnostics , and countermeasures. Clin. Infect. Dis. 21702,
1765–1771. doi: 10.1086/498155 Reynolds, M. G., Guagliardo, S. A. J., Nakazawa, Y. J., Doty, J. B., and Mauldin, M. R.
(2018). Understanding orthopoxvirus host range and evolution: from the enigmatic to
Ndodo, N., Ashcroft, J., Lewandowski, K., Yinka-Ogunleye, A., Chukwu, C., Ahmad, the usual suspects. Curr. Opin. Virol. 28, 108–115. doi: 10.1016/j.coviro.2017.11.012
A., et al. (2023). Distinct monkeypox virus lineages co-circulating in humans before
2022. Nat. Med. 29, 2317-2324. doi: 10.1038/s41591-023-02456-8 Rimoin, A. W., Kisalu, N., Kebela-Ilunga, B., Mukaba, T., Wright, L. L., Formenty, P.,
et al. (2011). Endemic human monkeypox, Republic of Congo, democratic 2001–2004.
Nigeria Centre for Disease Control (NCDC). (2022). UPDATE ON MONKEYPOX J. Phys. A Math. Theor. 44, 1689–1699. doi: 10.1088/1751-8113/44/8/085201
(MPX) IN NIGERIA. (Nigeria: Nigeria Centre for Disease Control (NCDC)).
Rimoin, A. W., Mulembakani, P. M., Johnston, S. C., Lloyd Smith, J. O., Kisalu, N. K.,
Noe, S., Zange, S., Seilmaier, M., Antwerpen, M. H., Fenzl, T., Schneider, J., et al. Kinkela, T. L., et al. (2010). Major increase in human monkeypox incidence 30 years
(2022). Clinical and virological features of first human monkeypox cases in Germany. after smallpox vaccination campaigns cease in the Democratic Republic of Congo. Proc.
Infection. 51, 265–270. doi: 10.1007/s15010-022-01874-z Natl. Acad. Sci. U. S. A. 107, 16262–16267. doi: 10.1073/pnas.1005769107
Nolen, L. D., Osadebe, L., Katomba, J., Likofata, J., Mukadi, D., Monroe, B., et al. Riopelle, J. C., Munster, V. J., and Port, J. R. (2022). Atypical and unique
(2015). Introduction of monkeypox into a community and household: Risk factors and transmission of monkeypox virus during the 2022 outbreak: an overview of the
zoonotic reservoirs in the democratic republic of the congo. Am. J. Trop. Med. Hyg. 93, current state of knowledge. Viruses 14, 2012. doi: 10.3390/v14092012
410–415. doi: 10.4269/ajtmh.15-0168
Rizk, J. G., Lippi, G., Henry, B. M., Forthal, D. N., and Rizk, Y. (2022). Prevention
Noyce, R. S., Lederman, S., and Evans, D. H. (2018). Construction of an infectious and treatment of monkeypox. Drugs 82, 957–963. doi: 10.1007/s40265-022-01742-y
horsepox virus vaccine from chemically synthesized DNA fragments. PloS One 13,
e0188453. doi: 10.1371/journal.pone.0188453 Ronquist, F., Teslenko, M., van der Mark, P., Ayres, D. L., Darling, A., Höhna, S.,
et al. (2012). MrBayes 3.2: efficient bayesian phylogenetic inference and model choice
Nuzzo, J. B., Borio, L. L., and Gostin, L. (2022). The WHO declaration of monkeypox as a across a large model space. Syst. Biol. 61, 539–542. doi: 10.1093/sysbio/sys029
global public health emergency. N. Engl. J. Med. 387, 679–691. doi: 10.1001/jama.2022.12513
Rubins, K. H., Hensley, L. E., Relman, D. A., and Brown, P. O. (2011). Stunned
Ortiz-Saavedra, B., Leó n-Figueroa, D. A., Montes-Madariaga, E. S., Ricardo- silence: Gene expression programs in human cells infected with monkeypox or vaccinia
Martı́nez, A., Alva, N., Cabanillas-Ramirez, C., et al. (2022). Antiviral treatment virus. PloS One 6, e15615. doi: 10.1371/journal.pone.0015615
against monkeypox: A scoping review. Trop. Med. Infect. Dis. 7, 369. doi: 10.3390/
tropicalmed7110369 Sah, R., Abdelaal, A., Reda, A., Katamesh, B. E., Manirambona, E., Abdelmonem, H.,
et al. (2022a). Monkeypox and its possible sexual transmission: where are we now with
O’Toole, A., Neher, R.A., Ndodo, N., Borges, V., Gannon, B., Gomes, J.P., et al. its evidence? Pathogens 11, 1–10. doi: 10.3390/pathogens11080924
(2023). APOBEC3 deaminase editing in MPXV as evidence for sustained human
transmission since at least 2016 Science. 382, 595–600. doi: 10.1126/science.adg8116 Sah, R., Mohanty, A., Reda, A., Padhi, B. K., and Rodriguez-Morales, A. J. (2022b). Stigma
during monkeypox outbreak. Front. Public Heal 10. doi: 10.3389/fpubh.2022.1023519
O’Toole, Á ., and Rambaut, A. (2022). Initial observations about putative APOBEC3
deaminase editing driving short-term evolution of MPXV since 2017 - Monkeypox / Saijo, M., Ami, Y., Suzaki, Y., Nagata, N., Iwata, N., Hasegawa, H., et al. (2009).
Evolution - Virological. Available at: https://virological.org/t/initial-observations- Virulence and pathophysiology of the Congo Basin and West African strains of
about-putative-apobec3-deaminase-editing-driving-short-term-evolution-of-mpxv- monkeypox virus in non-human primates. J. Gen. Virol. 90, 2266–2271.
since-2017/830 (Accessed February 3, 2023). doi: 10.1099/vir.0.010207-0

Frontiers in Cellular and Infection Microbiology 19 frontiersin.org

Alakunle et al. 10.3389/fcimb.2024.1360586

Salter, J. D., Bennett, R. P., and Smith, H. C. (2016). The APOBEC protein family: Tu, S.-L. (2015). The bioinformatic characterization of five novel poxviruses. (Oak Bay
united by structure, divergent in function. Trends Biochem. Sci. 41, 578-594. and Saanich, British Columbia, Canada: University of Victoria).
doi: 10.1016/j.tibs.2016.05.001 Uvarova, E. A., and Shchelkunov, S. N. (2001). Species-specific differences in the
Scarpa, F., Sanna, D., Azzena, I., Cossu, P., Locci, C., Angeletti, S., et al. (2022). structure of orthopoxvirus complement-binding protein. Virus Res. 81, 39–45.
Genetic variability of the monkeypox virus clade IIb B.1. J. Clin. Med. 11 6388. doi: 10.1016/S0168-1702(01)00332-X
doi: 10.3390/jcm11216388 Van Vliet, K., Mohamed, M. R., Zhang, L., Villa, N. Y., Werden, S. J., Liu, J., et al.
Schmidt, F. I., and Mercer, J. (2012). Vaccinia virus egress: Actin OUT with (2009). Poxvirus proteomics and virus-host protein interactions. Microbiol. Mol. Biol.
ClathrIN. Cell Host Microbe 12, 263–265. doi: 10.1016/j.chom.2012.08.007 Rev. 73, 730–749. doi: 10.1128/MMBR.00026-09
Schnierle, B. S. (2022). Monkeypox goes north: ongoing worldwide monkeypox Vaughan, A., Aarons, E., Astbury, J., Balasegaram, S., Beadsworth, M., Beck, C. R.,
infections in humans. Viruses 14, 1874. doi: 10.3390/v14091874 et al. (2018). Two cases of monkeypox imported to the United Kingdom, september
Seet, B. T., Johnston, J. B., Brunetti, C. R., Barrett, J. W., Everett, H., Cameron, C., 2018. Eurosurveillance 23, 1800509. doi: 10.2807/1560-7917.ES.2018.23.38.1800509
et al. (2003). Poxviruses and immune evasion. Annu. Rev. Immunol. 21, 377–423. Velavan, T. P., and Meyer, C. G. (2022). Monkeypox 2022 outbreak: An update.
doi: 10.1146/annurev.immunol.21.120601.141049 Trop. Med. Int. Heal. 27, 604–605. doi: 10.1111/tmi.13785
Senkevich, T. G., Yutin, N., Wolf, Y. I., Koonin, E. V., and Moss, B. (2021). Ancient Walker, M. C. (2022). Monkeypox Virus Hosts and Transmission Routes : A
gene capture and recent gene loss shape the evolution of orthopoxvirus-host interaction Systematic Review of a Zoonotic Pathogen. Available at: https://scholarworks.uark.
genes. MBio 12, e0149521. doi: 10.1128/mBio.01495-21 edu/biscuht/69%0AThis.
Shchelkunov, S. N., Totmenin, A. V., Babkin, I. V., Safronov, P. F., Ryazankina, O. I., Wang, L., Shang, J., Weng, S., Aliyari, S. R., Ji, C., Cheng, G., et al. (2022). Genomic
Petrov, N. A., et al. (2001). Human monkeypox and smallpox viruses: Genomic annotation and molecular evolution of monkeypox virus outbreak in 2022. J. Med.
comparison. FEBS Lett. 509, 66–70. doi: 10.1016/S0014-5793(01)03144-1 Virol. 95 (1), e28036. doi: 10.1002/jmv.28036
Shchelkunov, S. N., Totmenin, A. V., Safronov, P. F., Mikheev, M. V., Gutorov, V. V., Wassenaar, T. M., Wanchai, V., and Ussery, D. W. (2022). Comparison of
Ryazankina, O. I., et al. (2002). Analysis of the monkeypox virus genome. Virology 297, Monkeypox virus genomes from the 2017 Nigeria outbreak and the 2022 outbreak. J.
172–194. doi: 10.1006/viro.2002.1446 Appl. Microbiol. 133 (6), 3690–3698. doi: 10.1111/jam.15806
Shen-Gunther, J., Cai, H., and Yufeng, W. (2023). A customized monkeypox virus Weaver, J. R., and Isaacs, S. N. (2008). Monkeypox virus and insights into its
genomic database (MPXV DB v1.0) for rapid sequence analysis and phylogenomic immunomodulatory proteins. Immunol. Revolut. 225, 96–113. doi: 10.1111/j.1600-
discoveries in CLC microbial genomics. Viruses 15, 40. doi: 10.3390/v15010040 065X.2008.00691.x.Monkeypox
Shisler, J. L., and Jin, X.-L. (2004). The vaccinia virus K1L gene product inhibits host Wenner, H. A., Macasaet, F. D., Kamitsuka, P. S., and Kidd, P. (1968). Monkey pox. I.
NF-kB activation by preventing IkBa Degradation. J. Virol. 78, 3553–3560. Clinical, virologic and immunologic studies. Am. J. Epidemiol. 87, 551–566.
doi: 10.1128/JVI.78.7.3553-3560.2004 doi: 10.1093/oxfordjournals.aje.a120846
Siegrist, E. A., and Sassine, J. (2022). Antivirals with activity against monkeypox: A White, S. D., and Jacobs, B. L. (2012). The amino terminus of the vaccinia virus E3
clinically oriented review. Clin. Infect. Dis. 76, 155–164. doi: 10.1093/cid/ciac622 protein is necessary to inhibit the interferon response. J. Virol. 86, 5895–5904.
Singhal, T., Kabra, S. K., and Lodha, R. (2022). Monkeypox : A review. Indian J. doi: 10.1128/JVI.06889-11
Pediatr. 89, 955–960. doi: 10.1007/s12098-022-04348-0 Wolffe, E. J., Weisberg, A. S., and Moss, B. (1998). Role for the vaccinia virus A36R
Sivan, G., Weisberg, A. S., Americo, J. L., and Moss, B. (2016). Retrograde transport outer envelope protein in the formation of virus-tipped actin-containing microvilli and
from early endosomes to the trans -golgi network enables membrane wrapping and cell-to-cell virus spread. Virology 244, 20–26. doi: 10.1006/viro.1998.9103
egress of vaccinia virus virions. J. Virol. 90, 8891–8905. doi: 10.1128/JVI.01114-16 World Health Organization. (2022). 2022 Mpox (Monkeypox) Outbreak: Global
Sklenovská, N., and Van Ranst, M. (2018). Emergence of monkeypox as the most important Trends. Available at: https://worldhealthorg.shinyapps.io/mpx_global/ (Accessed
orthopoxvirus infection in humans. Front. Public Heal. 6. doi: 10.3389/fpubh.2018.00241 February 2, 2023).
Slowinski, J. B. (2001). Molecular polytomies. Mol. Phylogenet. Evol. 19, 114-120. World Health Organization. (2022a). Disease Outbreak News; Multi-country
doi: 10.1006/mpev.2000.0897 monkeypox outbreak in non-endemic countries. Available at: https://www.who.int/
emergencies/disease-outbreak-news/item/2022-DON385 (Accessed February 2, 2023).
Song, H., Josleyn, N., Janosko, K., Skinner, J., Reeves, R. K., Cohen, M., et al. (2013).
Monkeypox virus infection of rhesus macaques induces massive expansion of natural World Health Organization. (2022b). Multi-country monkeypox outbreak: situation
killer cells but suppresses natural killer cell functions. PloS One 8, e77804. doi: 10.1371/ update. Available at: https://www.who.int/emergencies/disease-outbreak-news/item/
journal.pone.0077804 2022-DON393 (Accessed February 2, 2023).
Sousa, Á .F.L.d., Sousa, A.R.d., and Fronteira, I. (2022). Monkeypox: between Xiang, Y., and White, A. (2022). Monkeypox virus emerges from the shadow of its
precision public health and stigma risk. Rev. Bras. Enferm. 75, e750501. doi: 10.1590/ more infamous cousin: family biology matters. Emerg. Microbes Infect. 11, 1768–1777.
0034-7167.2022750501 doi: 10.1080/22221751.2022.2095309
Stephen, R., Alele, F., Olumoh, J., Tyndall, J., and Okeke, M. I. (2022). The epidemiological Xuan, D. T. M., Yeh, I. J., Wu, C. C., Su, C. Y., Liu, H. L., Chiao, C. C., et al. (2022).
trend of monkeypox and monkeypox-varicella zoster viruses co-infection in North-Eastern Comparison of transcriptomic signatures between monkeypox-infected monkey and
Nigeria. Front. Public Heal. 10, 1066589. doi: 10.3389/fpubh.2022.1066589 human cell lines. J. Immunol. Res. 2022, 3883822. doi: 10.1155/2022/3883822
Stuart, J. H., Sumner, R. P., Lu, Y., Snowden, J. S., and Smith, G. L. (2016). Vaccinia virus Ye, F., Song, J., Zhao, L., Zhang, Y., Xia, L., Zhu, L., et al. (2019). Molecular evidence
protein C6 inhibits type I IFN signalling in the nucleus and binds to the transactivation of human monkeypox virus infection, Sierra Leone. Emerg. Infect. Dis. 25, 1220–1222.
domain of STAT2. PloS Pathog. 12, 1–24. doi: 10.1371/journal.ppat.1005955 doi: 10.3201/eid2506.180296
Suchard, M. A., Lemey, P., Baele, G., Ayres, D. L., Drummond, A. J., and Rambaut, A. Yeh, T.-Y., and Contreras, G. P. (2022). Recombination shapes 2022 monkeypox
(2018). Bayesian phylogenetic and phylodynamic data integration using BEAST 1.10. outbreak. Med. 3, 824–826. doi: 10.1101/2022.08.09.22278589
Virus Evol. 4, 1–5. doi: 10.1093/ve/vey016 Yeh, T.-Y., Hsieh, Z.-Y., Feehley, M.C., Feehley, P.J., Contreas, G.P., Su, Y.-C., et al.
Sun, S.-C. (2017). The non-canonical NF-kB pathway in immunity and (2022). Recombination shapes the 2022 monkeypox ( mpox ) outbreak. Med 3, 824–826.
inflammation. Nat. Rev. Immunol. 17, 545–558. doi: 10.1038/nri.2017.52.The doi: 10.1016/j.medj.2022.11.003
Tchokoteu, P. F., Kago, I., Tetanye, E., Ndoumbe, P., Pignon, D., and Mbede, J. Yinka-Ogunleye, A., Aruna, O., Dalhat, M., Ogoina, D., McCollum, A., Disu, Y., et al.
(1991). Variola or a severe case of varicella? A case of human variola due to monkeypox (2019). Outbreak of human monkeypox in Nigeria in 2017–18: a clinical and epidemiological
virus in a child from the Cameroon. Ann. Soc. Belg Med. Trop. 71, 123–128. report. Lancet Infect. Dis. 19, 872–879. doi: 10.1016/S1473-3099(19)30294-4
Titanji, B. K., Tegomoh, B., Nematollahi, S., Konomos, M., and Kulkarni, P. A. Yinka-Ogunleye, A., Aruna, O., Ogoina, D., Aworabhi, N., Eteng, W., Badaru, S.,
(2022). Monkeypox: A contemporary review for healthcare professionals. Open Forum et al. (2018). Reemergence of human monkeypox in Nigeri. Emerg. Infect. Dis. 24,
Infect. Dis. 9, 1–13. doi: 10.1093/ofid/ofac310 1149–1151. doi: 10.3201/eid2406.180017

Frontiers in Cellular and Infection Microbiology 20 frontiersin.org