REVIEW

CURRENT
OPINION New findings in the pathogenesis of leprosy and
implications for the management of leprosy
Anastasia Polycarpou a, Stephen L. Walker a, and Diana N. Lockwood a,b

Purpose of review
This review focuses on recent work in leprosy pathogenesis. New research of both innate and adaptive
immune responses to Mycobacterium leprae is described. The proposition that Mycobacterium lepromatosis
is a new species causing leprosy is discussed.
Recent findings
Modulation of the lipid metabolism and reprogramming of adult Schwann cells have both been suggested
as mechanisms used by M. leprae to disseminate the disease. New markers associated with localized,
disseminated disease or the occurrences of leprosy reactions include the human interferons, CD163,
microRNA-21, NOD2, galectin-3 and toll-like receptor 4. The role of keratinocytes instead of macrophages
is underlined in the pathogenesis of leprosy. Adaptive immunity reports focus on the role of T regulatory
cells and cytokines secreted by T helper cells in leprosy. Finally, a newly identified species named M.
lepromatosis has been detected in patients with leprosy and severe erythema nodosum leprosum.
Summary
Novel biological pathways have been identified to be associated with the clinical phenotype of leprosy or
the occurrence of leprosy reactions. Future work should include larger numbers of clinical samples from
across the leprosy spectrum in order to give new insights in the pathogenesis and management of the
disease.
Keywords
erythema nodosum leprosum, leprosy, Mycobacterium leprae, Mycobacterium lepromatosis, type 1 reactions

INTRODUCTION erythema nodosum leprosum (ENL) is considered an

Leprosy is a chronic granulomatous disease affecting immune complex-mediated complication of leprosy
mainly the skin and peripheral nerves, which is [5], characterized by crops of tender erythematous
caused by infection with the intracellular bacterium nodules, systemic manifestations such as fever,
Mycobacterium leprae [1]. There are still more than malaise and inflammation elsewhere producing iri-
200 000 new leprosy cases registered globally each tis, lymphadenitis, orchitis, arthritis and neuritis [6].
year [2]. The pathology of leprosy is determined by Treatment of leprosy reactions with corticosteroids
the immune response to M. leprae, resulting in a is not always effective in limiting the nerve function
clinical range from tuberculoid through borderline impairment, which may lead to disability and
forms to lepromatous leprosy as classified by Ridley deformity [7].
and Jopling [3]. Multidrug therapy (MDT) compris- This review focuses on the pathogenesis of M.
ing a combination of the drugs dapsone, rifampicin leprae infection and leprosy reactions, identification
and clofazimine is successfully used in treating
the infection. Despite MDT, leprosy can be compli- a
Department of Clinical Research, Faculty of Infectious and Tropical
cated by acute inflammatory episodes called leprosy
Diseases, London School of Hygiene and Tropical Medicine and bThe
reactions. Hospital of Tropical Diseases, London, UK
Type 1 or reversal reaction (T1R) affects skin Correspondence to Anastasia Polycarpou, Department of Clinical
lesions and nerves and is considered a delayed Research, Faculty of Infectious and Tropical Diseases, London School
hypersensitivity reaction characterized by the of Hygiene and Tropical Medicine, Keppel street, London WC1E 7HT,
infiltration of skin and nerve lesions by CD4þ UK. Tel: +442 076 122 642; e-mail: Anastasia.Polycarpou@lshtm.ac.uk
lymphocytes secreting high levels of interferon Curr Opin Infect Dis 2013, 26:413–419
(IFN)-g and tumor necrosis factor-a [4]. Type 2 or DOI:10.1097/QCO.0b013e3283638b04

0951-7375 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-infectiousdiseases.com

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Tropical and travel-associated diseases

protein kinase on Ser565, both serine residues

KEY POINTS required for the function of HSL. Interestingly, it
 M. leprae interacts with the host cell lipid metabolism in has been described that 1 h after infection with M.
order to favor intracellular bacterial survival and this leprae, HSL expression is suppressed and there is also
can be modulated by clofazimine. decreased phosphorylation of the two serine resi-
dues [14].
 M. leprae infection may be spread to other tissues by
The commonest laboratory test for diagnosis
reprogramming of adult Schwann cells.
and classification of leprosy patients is the slit-skin
 The expression of NOD2 is associated with tuberculoid smear in which microscopy is used to identify the
leprosy by inducing differentiation of monocytes into presence of acid-fast bacilli. In the study of Tanigawa
dendritic cells whereas the expression of galectin-3 is et al. [14], HSL expression was undetectable in the
associated with lepromatous leprosy by promoting
slit-skin smear specimens from five lepromatous and
differentiation of monocytes into macrophages.
four of seven borderline lepromatous patients. The
 Keratinocytes, but not macrophages, may respond to result suggests that the low HSL levels in dissemi-
M. leprae by upregulating b-defensin 3, induced by nated disease could provide a new molecular mech-
type 1 reactions and suppressed by corticosteroids. anism for M. leprae to preserve host lipids. Increase
 M. lepromatosis may be a new causative agent for of HSL occurred in slit-skin smears of two borderline
diffuse lepromatous leprosy and leprosy reactions, but patients experiencing T1Rs and four patients after
further investigation is required. successful treatment with MDT [14]. The same
group showed that clofazimine is the drug of
MDT causing this effect in vitro, as it attenuated
the mRNA and protein levels of ADRP, whereas
of new biomarkers for susceptibility and prognosis, increased those of HSL in M. leprae-infected human
and it summarizes recent literature. premonocytic THP-1 cells [15]. Clofazimine not
only antagonizes the effects of M. leprae on the
modulation of ADRP and HSL, but also leads to a
MYCOBACTERIUM LEPRAE decrease of lipid droplet accumulation driven by M.
PATHOGENESIS leprae infection, modulating lipid metabolism in M.
Recent studies have investigated how M. leprae influ- leprae-infected macrophages [15]. Rifampicin and
ences the host cell lipid metabolism in order to favor dapsone did not significantly affect ADRP or HSL
intracellular bacterial survival and how this can be expression levels [15]. ADRP and HSL mRNA and
modulated by MDT. Moreover, a new model for protein levels were evaluated in slit-skin smear and
leprosy dissemination by reprogramming adult skin biopsy specimens from a leprosy patient before
Schwann cells has been identified. and after treatment, showing decrease of ADRP and
increase of HSL after MDT [15]. This study suggests a
new mechanism of action for the drug clofazimine.
Mycobacterium leprae and host lipid A future study including more clinical samples
metabolism would be useful in order to correlate ADRP and
The histology of lepromatous leprosy lesions is HSL expression with the clinical course of leprosy.
characterized by foamy macrophages due to the
accumulation of host-derived lipids [8–9]. Lipid
droplets are lipid storage organelles found in all cell Mycobacterium leprae and reprogramming
types. It has been shown that M. leprae induces lipid adult cells
droplet biogenesis in macrophages [9] and Schwann The neural tropism of M. leprae is due to its binding
cells [10], creating a favorable niche for its own to the G domain of the bridging molecule laminin-
survival. Adipophilin/adipose differentiation- a2 [16], and a-dystroglycan serves as the Schwann
related protein (ADRP) has an essential role in fatty cell receptor for M. leprae [17]. M. leprae induces
acid transport, inducing lipid accumulation [11], demyelination of myelinated Schwann cells, mak-
and has opposing functions to hormone-sensitive ing Schwann cells more prone to invasion by the
lipase (HSL), which favors lipid degradation [12]. bacillus, in a Rag1
/
mouse model lacking mature B
Previous work has shown that M. leprae increases the and T lymphocytes [18]. This demyelination process
expression of ADRP in macrophages [13]. Recent by leprosy bacilli is mediated by tyrosine kinase
work by Tanigawa et al. [14] shows that the expres- signaling through the ErbB2 receptor [19]. It is
sion of HSL can be suppressed by live but not dead not known how colonization of Schwann cells
M. leprae in macrophages. Protein kinase A phos- by M. leprae leads to the spread of infection to
phorylates HSL on Ser563 and 50 -AMP-activated other tissues. The in-vitro and murine in-vivo study

414 www.co-infectiousdiseases.com Volume 26  Number 5  October 2013

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 New findings in the pathogenesis of leprosy Polycarpou et al.

&&
by Masaki et al. [20 ] investigated further the inter- by downregulating key genes in the toll-like recep-
actions of M. leprae with Schwann cells and tor (TLR)-induced antimicrobial pathway [21],
suggested a novel model to explain the spread of which are triggered in monocytes/macrophages
the infection. The study suggested that M. leprae when they detect M. leprae infection [22]. This study
bacilli interact with and change the fate of Schwann supports the finding that monocytes/macrophages
cells to progenitor/stem cells with mesenchymal on detecting M. leprae trigger the vitamin D-depend-
&&
characteristics [20 ]. The cell reprogramming fol- ent antimicrobial pathway [22], but that this
lows the silencing of the master regulation of response is at the same time inhibited by the upreg-
&&
Schwann cell lineage Sox10 [20 ]. M. leprae, there- ulation of microRNA-21 by M. leprae itself [21].
fore, promotes dissemination of disease through Human interferons (IFN) are classified according
two mechanisms: direct differentiation of Schwann to the type of receptor through which they signal.
cells to mesenchymal tissues and formation of gran- Therefore, IFN-a and IFN-b are type I IFNs, whereas
&&
uloma-like structures that release bacteria-bearing IFN-g is type II IFN. A study by Teles et al. [23 ] used
&&
macrophages [20 ]. This study increases our under- microarray data analysis to associate type I and type
standing of adult tissue cell plasticity and indicates II IFN genes with the outcome of host response in
for the first time that a bacterium may lead to leprosy. The study showed that IFN-g-specific genes
reprogramming of adult cells into stem cells. How- were preferentially elevated in borderline tubercu-
ever, in order to demonstrate this effect, Schwann loid lesions and T1Rs, and IFN-b and its downstream
cells were infected with a very high number of M. genes, such as interleukin (IL)-10, were more
&&
leprae bacilli (multiplicity of infection >50) with detected in lepromatous leprosy lesions [23 ]. In
&&
>90% infection efficiency [20 ]. Moreover, the addition, mRNA was isolated from skin lesions of 10
methodology used nude mice that lack T cells, over- lepromatous leprosy, 10 borderline tuberculoid and
simplifying the inflammatory microenvironment to 10 T1Rs patients and RT-PCR was performed, which
&&
predominantly macrophages [20 ]. Therefore, showed higher expression of IFN-b mRNA in lep-
although the study describes an attractive in-vitro romatous leprosy lesions and IFN-g mRNA in bor-
model to explain M. leprae pathogenesis, more derline tuberculoid and T1R lesions. Protein
research is needed before conclusions can be expression of IFN-b was also more evident in lep-
extrapolated to human disease. romatous leprosy lesions and was localized in
macrophages. When IFN-g-induced genes in border-
line tuberculoid lesions were analyzed, several anti-
INNATE IMMUNITY microbial pathways were revealed, including the
Several recent studies compared the immune vitamin D-dependent antimicrobial pathway
&&
response of borderline tuberculoid with leproma- [23 ]. This pathway can be inhibited by IFN-b
tous leprosy patients, to identify new biomarkers and IL-10, and therefore they suggested that in
and biological pathways associated with the clinical leprosy pathogenesis there is an inverse correlation
phenotype of the disease. New potential biomarkers between IFN-b and IFN-g expression programs and
for T1Rs have been identified, but there is still a lack that altering the IFN balance by blocking IFN-b or
of studies on ENL. enhancing IFN-g responses could prove to be a new
&&
therapeutic intervention [23 ].
CD163 is a monocyte/macrophage receptor that
Borderline tuberculoid vs. lepromatous recognizes hemoglobin–haptoglobin complexes
leprosy [24] and it has been suggested to function as an
Liu et al. [21] used microarrays to reveal increased alternative receptor for M. leprae entry into host cells
gene expression of 13 microRNAs in skin biopsy [25]. Therefore, M. leprae could induce CD163 in
specimens from five lepromatous leprosy vs. six order to create a favorable environment for its own
borderline tuberculoid untreated patients, with survival [25]. Data supporting this hypothesis come
microRNA-21 being the most highly expressed in from Brazil, where six lepromatous leprosy and six
lepromatous leprosy vs. borderline tuberculoid borderline tuberculoid patients were compared.
lesions. Real-time PCR (RT-PCR) demonstrated Lepromatous macrophages were shown to express
the high expression of microRNA-21 in the lepro- higher mRNA and protein levels of the scavenger
matous leprosy lesions, and fluorescent in-situ receptor CD163, whereas increased levels of CD163
hybridization revealed that the microRNA-21- in the sera of lepromatous patients were detected
positive cells in the sections were located within [25]. The higher expression of CD163 observed was
the granulomas [21]. The study also demonstrated in parallel with the expression of the tryptophan
that microRNA-21 inhibited gene expression of rate-limiting enzyme indoleamine 2,3-dioxygenase
the vitamin D-dependent antimicrobial pathway (IDO) [25]. Hemoglobin induces the expression of

0951-7375 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-infectiousdiseases.com 415

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Tropical and travel-associated diseases

IDO in dendritic cells, supporting the interaction Another study performed by our group included
between CD163 and IDO [26]. Another Brazilian 21 patients with cutaneous involvement of a leprosy
study, addressing the role of IDO in leprosy, had T1R and showed firstly that TLR2 and TLR4 genes
demonstrated high IDO protein expression in skin and protein were expressed in lesions of T1Rs and
biopsies of lepromatous leprosy patients, whereas secondly that both gene and protein expression of
very few IDOþ cells were seen in lesions from border- TLR2 and TLR4 were significantly reduced during
line tuberculoid patients and patients undergoing corticosteroid treatment [31]. This is the first study
T1Rs [27]. to examine the expression of TLR2 and TLR4 in vivo
&
Schenk et al. [28 ] compared the expression of in individuals experiencing T1Rs and leads the way
the receptor nucleotide-binding oligomerization to further research of TLRs in the pathophysiology
domain-containing protein 2 (NOD2) and IL-32 of leprosy reactions [31].
with the clinical presentation of leprosy, as NOD2þ
cells and IL-32þ cells were three and eight-fold
higher, respectively, in borderline tuberculoid than ADAPTIVE IMMUNITY
lepromatous leprosy skin lesions. Activation of T cell anergy is considered a characteristic of lep-
NOD2 with its ligand muramyl dipeptide has been romatous leprosy patients [32]. Recent work on the
shown to induce differentiation of monocytes into role of T regulatory cells (Tregs) in leprosy and the
& &
dendritic cells [28 ]. Conversely, Chung et al. [29 ] recently identified IL17-producing T helper (Th17)
studied galectin-3, a protein predominantly cells that emerged as a new subset of T helper cells
expressed on cells of the monocyte/macrophage is discussed.
lineage, and showed galectin-3 to be associated with
lepromatous leprosy as it was expressed strongly in
80–95% of cells in skin lesions from three leprom- T cell responses
atous patients, whereas it was almost undetectable Lsr2 is a 15kDa basic protein of M. leprae, and Lsr2
in lesions from three tuberculoid patients, in which peptides were previously shown to be recognized by
only 10% of the cells were weakly galectin-3þ. How- T cells and antibodies of tuberculoid and leproma-
ever, live M. leprae did not increase the expression of tous patients [33]. Using 22 synthetic overlapping
galectin-3 mRNA or protein in human monocytes. and end-to-end peptides spanning the Lsr2
To explain the immune unresponsiveness observed sequence, a recent study investigated the T cell
in lepromatous patients, Chung et al. proposed that functions measured by lymphoproliferation and
in lepromatous lesions monocytes are promoted to IFN-g release [34]. The study showed that anergic
differentiate into macrophages instead of to den- lepromatous patients, who did not show in-vitro
dritic cells. Therefore, if galectin-3, demonstrated to responses to M. leprae antigens, did respond to the
be highly expressed in lepromatous leprosy lesions, multiple T cell epitopes of Lsr2 protein [34]. Another
also promotes the differentiation of monocytes into study addressed the role of Lsr2 in eliciting lympho-
macrophages rather than dendritic cells, then galec- proliferation and IFN-g release during T1Rs and ENL
tin-3 could potentially become a target for future [35] and showed that even 6 months postreactions,
interventions promoting host defense in humans. patients continued to respond to Lsr2 and its pep-
tides, suggesting that Lsr2 could be a promising
candidate disease marker in the diagnosis of leprosy
Pathogenesis of type 1 reactions reactions [35].
b-defensin 3 is an antimicrobial peptide serving as
the first line of defense against many bacteria,
viruses and fungi. A study performed by our group T regulatory cells
looked at the association of the human b-defensin 3 A study by Palermo et al. [36] addressed the role of
&
with T1Rs [30 ]. Using real-time PCR and immuno- Tregs in leprosy. Tregs suppress the functions of
histochemistry, human b-defensin 3 was induced in effector T cells, but in infection this suppression
&
T1Rs and suppressed by corticosteroids [30 ]. Inter- could result in reduced effectiveness of immune
estingly, keratinocytes, but not macrophages, upre- response against the pathogen. Palermo et al. admit-
gulated human b-defensin 3 in response to M. leprae ted 28 consecutive newly diagnosed leprosy patients
&
in vitro [30 ]. Although keratinocytes play an import- that were dichotomized as lepromatous leprosy
ant role in immune homeostasis and innate immun- (borderline lepromatous and lepromatous leprosy)
ity, they are often thought as part of the barrier and tuberculoid leprosy patients (borderline tuber-
rather than an immune organ. This study shows the culoid and tuberculoid leprosy). Using flow cytom-
potential importance of epidermal processes as well etry in peripheral blood mononuclear cells (PBMCs)
as dermal ones in the pathophysiology of leprosy. and immunohistochemistry in skin lesions, Palermo

416 www.co-infectiousdiseases.com Volume 26  Number 5  October 2013

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 New findings in the pathogenesis of leprosy Polycarpou et al.

et al. found significant increase of Tregs in leprom- T1Rs or to demonstrate a pathogenic-causative

atous patients compared with tuberculoid patients effect of IL-17F in leprosy complications. Interest-
not only in blood but also in situ [36]. Tregs were ingly, although mycobacteria have been previously
rarely observed in tuberculoid lesions [36]. IL-10 and reported to stimulate the production of IL-17 [43],
cytotoxic T-lymphocyte antigen 4, but not trans- when samples were classified based on the bacterio-
forming growth factor-b, were increased in leprom- logical index into groups, an inversely proportional
atous rather than tuberculoid lesions [36]. These association of the IL-17F levels with the bacterio-
results contradict a previous study that showed a logical index was shown [42].
higher frequency of circulating Tregs in the periph- The study by Martiniuk et al. [44] investigated
eral blood of tuberculoid than lepromatous patients the Th17 subset in skin biopsies of seven ENL
[37] This study suggests that controlling the balance patients from Nepal treated with thalidomide for
of Tregs function may be a potential new strategy in 21 days. RNA was extracted followed by RT-PCR.
managing leprosy. Martiniuk et al. studied the relative gene expression
patterns for 20 genes in the Th17 pathway and
showed that thalidomide both suppresses some
T helper 17 cytokines inflammatory components of Th17, while enhanc-
IL-17 was first described as a proinflammatory cyto- ing those involved in cell-mediated immunity [44].
kine produced by T cells [38]. Later, it was discovered IL-17A, the hallmark cytokine of Th17, was detected
that the cell sources of IL-17 are in fact the Th17 before and after thalidomide treatment, suggesting
cells, which are developmentally distinct forms of that IL-17A could possibly be upregulated by thali-
Th1 and Th2 cells [38]. IL-17, now referred as IL-17A, domide treatment of ENL [44]. They also suggested
is a member of the IL-17 family, which includes IL- IDO to be investigated in the future as a potential
17A-F [38]. IL-17 overexpression has been associated target of thalidomide as it was upregulated by IFN-g
with diseases such as rheumatoid arthritis, psoriasis, in ENL, whereas it was downregulated following
Crohn disease and multiple sclerosis. thalidomide treatment of ENL [44]. IDO had been
The first published study on IL-17A in biopsies implicated in the past as inhibiting the Th17
from active lesions of 38 leprosy patients and 15 responses in a mouse model of Mycobacterium tuber-
healthy controls demonstrated an abrogated mRNA culosis [45]. IDO expression has been demonstrated
IL-17A response in all leprosy patients, as compared to be in parallel with the expression of the receptor
to controls [39]. In addition, IL-17A mRNA and CD163 [25], suggested to be an alternative receptor
IL23p19 mRNA in lepromatous leprosy patients for M. leprae entry into host cells [25].
had an inverse linear correlation with bacteriologi-
cal index, the standard method for assessment of
M. leprae mycobacterial load based on a logarithmic MYCOBACTERIUM LEPROMATOSIS:
scale. The observed inverse linear correlation with A NEW SPECIES CAUSING LEPROSY?
bacteriological index was not seen for the related A diffuse form of lepromatous leprosy (DLL), also
cytokine IL-6 [39]. However, circulating IL-17A was known as Lucio’s leprosy, predominantly seen in
undetectable in both patients and controls [39]. Mexico and Central America, is characterized clin-
IL-17F acts as a mediator in the delayed-type ically by diffuse, nonnodular cutaneous infiltration
hypersensitivity reactions by induction of IFN-g- and pathologically by mycobacterial invasion of the
inducible protein 10 in a model of airway inflam- endothelium and vasculopathy in the dermis and
mation, which includes bronchial epithelial cells subcutis [6]. Lucio’s phenomenon may develop in
[40]. IL-17F also mediates inflammatory responses DLL patients when the skin becomes ulcerated lead-
against certain intracellular pathogens [41]. ing to secondary bacterial infections, sepsis and
Chaitanya et al. [42] analyzed the serum circulatory death. Lucio’s phemomenon is associated with
levels of IL-17F in patients with T1Rs, ENL and with necrosis of arterioles.
nonreactional leprosy of all Ridley–Jopling types. In 2008 Han et al. [46], using genome sequenc-
This Indian study included 80 active untreated lep- ing, isolated a novel Mycobacterium species from
rosy cases with T1R, 21 cases with ENL, 80 nonreac- two Mexican patients with DLL. It was named
tional leprosy cases and 94 nonleprosy cases. ELISA Mycobacterium lepromatosis and was described to
was used to measure the IL-17F levels in the serum. diverge from a common ancestor with M. leprae
The study demonstrated the mean serum levels of [47]. Since then, several case reports of leprosy
IL-17F to be significantly higher in the T1R group patients having infection with M. lepromatosis
when compared with nonreactional and nonleprosy have been published [48–50]. Another study by
groups [42]. More research is needed to investigate a Han et al. [51] using PCR tested for M. lepromatosis
possible role of IL-17F as a potential biomarker of and M. leprae DNA, which was extracted from

0951-7375 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-infectiousdiseases.com 417

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Tropical and travel-associated diseases

archived skin biopsy specimens of 120 leprosy REFERENCES AND RECOMMENDED

cases from Mexico. Han et al. [51] supported READING
Papers of particular interest, published within the annual period of review, have
that M. lepromatosis is the main cause of leprosy been highlighted as:
in Mexico as in their study, and it had been associ- & of special interest
&& of outstanding interest
ated with far more leprosy cases and other clinical Additional references related to this topic can also be found in the Current
forms of leprosy than DLL. In some individuals World Literature section in this issue (p. 485).
coinfection with M. leprae and M. lepromatosis was 1. Britton WJ, Lockwood DN. Leprosy. Lancet 2004; 363:1209–1219.
observed [51]. In addition, a recent study from the 2. World Health Organization. Global leprosy situation. World Health Organiza-
tion; 2012.
same group described two Mexican leprosy 3. Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-
patients, one with ENL and the other with Lucio’s group system. Int J Lepr Other Mycobact Dis 1966; 34:255–273.
4. Sarno EN, Grau GE, Vieira LM, Nery JA. Serum levels of tumour necrosis
phenomenon from which M. lepromatosis was iso- factor-alpha and interleukin-1 beta during leprosy reactional states. Clin Exp
lated from the lymph node tissue [52]. However, Immunol 1991; 84:103–108.
5. Wemambu SN, Turk JL, Waters MF, Rees RJ. Erythema nodosum leprosum: a
Gillis et al. [53] have noted that the experiments and clinical manifestation of the arthus phenomenon. Lancet 1969; 2:933–935.
data need confirmation to prove that M. leproma- 6. Kahawita IP, Lockwood DN. Towards understanding the pathology of erythe-
ma nodosum leprosum. Trans R Soc Trop Med Hyg 2008; 102:329–337.
tosis is a new leprosy-causing species. We still do not 7. van Veen NH, Nicholls PG, Smith WC, Richardus JH. Corticosteroids for
know whether the investigators have isolated a treating nerve damage in leprosy. Lepr Rev 2008; 79:361–371.
8. Cruz D, Watson AD, Miller CS, et al. Host-derived oxidized phospholipids and
variant of M. leprae or whether they have isolated HDL regulate innate immunity in human leprosy. J Clin Invest 2008;
DNA from a bacterium closely related to M. leprae 118:2917–2928.
9. Mattos KA, D’Avila H, Rodrigues LS, et al. Lipid droplet formation in leprosy:
that is associated with M. leprae infection but may Toll-like receptor-regulated organelles involved in eicosanoid formation and
not cause of the disease itself [53]. Mycobacterium leprae pathogenesis. J Leukoc Biol 2010; 87:371–384.
10. Mattos KA, Oliveira VG, D’Avila H, et al. TLR6-driven lipid droplets in Myco-
bacterium leprae-infected Schwann cells: immunoinflammatory platforms
associated with bacterial persistence. J Immunol 2011; 187:2548–2558.
11. Imamura M, Inoguchi T, Ikuyama S, et al. ADRP stimulates lipid accumulation
CONCLUSION and lipid droplet formation in murine fibroblasts. Am J Physiol Endocrinol
Metab 2002; 283:E775–E783.
Several recent studies focused on the identification 12. Egan JJ, Greenberg AS, Chang MK, et al. Mechanism of hormone-stimulated
of candidate biomarkers associated with the clinical lipolysis in adipocytes: translocation of hormone-sensitive lipase to the lipid
storage droplet. Proc Natl Acad Sci U S A 1992; 89:8537–8541.
phenotype of the disease or the occurrence of lep- 13. Tanigawa K, Suzuki K, Nakamura K, et al. Expression of adipose differentia-
rosy reactions. New candidate proteins or biological tion-related protein (ADRP) and perilipin in macrophages infected with
Mycobacterium leprae. FEMS Microbiol Lett 2008; 289:72–79.
pathways were identified and these studies shed 14. Tanigawa K, Degang Y, Kawashima A, et al. Essential role of hormone-
light on the pathogenesis of leprosy, with possible sensitive lipase (HSL) in the maintenance of lipid storage in Mycobacterium
leprae-infected macrophages. Microb Pathog 2012; 52:285–291.
implications for other mycobacterial diseases. 15. Degang Y, Akama T, Hara T, et al. Clofazimine modulates the expression of
Future studies should include more clinical samples lipid metabolism proteins in Mycobacterium leprae-infected macrophages.
PLoS Negl Trop Dis 2012; 6:e1936.
in order to study the ability of M. leprae to modulate 16. Rambukkana A, Salzer JL, Yurchenco PD, Tuomanen EI. Neural targeting of
lipid metabolism, by measuring the ADRP and HSL Mycobacterium leprae mediated by the G domain of the laminin-alpha2 chain.
Cell 1997; 88:811–821.
levels in patient samples. More research needs to be 17. Rambukkana A, Yamada H, Zanazzi G, et al. Role of alpha-dystroglycan as a
undertaken in vivo to investigate whether M. leprae Schwann cell receptor for Mycobacterium leprae. Science 1998; 282:2076–
2079.
reprograms Schwann cells and uses this mechanism 18. Rambukkana A, Zanazzi G, Tapinos N, Salzer JL. Contact-dependent demye-
to spread to other tissues. Larger studies to identify lination by Mycobacterium leprae in the absence of immune cells. Science
2002; 296:927–931.
biomarkers and pathophysiological pathways 19. Tapinos N, Ohnishi M, Rambukkana A. ErbB2 receptor tyrosine kinase
should use patients across the Ridley–Jopling spec- signaling mediates early demyelination induced by leprosy bacilli. Nat Med
2006; 12:961–966.
trum. Promising candidate biomarkers have been 20. Masaki T, Qu J, Cholewa-Waclaw J, et al. Reprogramming adult Schwann
identified and should be further investigated && cells to stem cell-like cells by leprosy bacilli promotes dissemination of
infection. Cell 2013; 152:51–67.
include the human IFNs and IDO/CD163 expres- This is the first study that shows reprogramming of adult cells into stem cells with
sion. Galectin-3 has also arisen as new potential the use of a bacterium, in specific M. leprae.
21. Liu PT, Wheelwright M, Teles R, et al. MicroRNA-21 targets the vitamin D-
target for future interventions. More work should dependent antimicrobial pathway in leprosy. Nat Med 2012; 18:267–273.
clarify the role of Tregs and Th17 cytokines in 22. Montoya D, Cruz D, Teles RM, et al. Divergence of macrophage phagocytic
and antimicrobial programs in leprosy. Cell Host Microbe 2009; 6:343–353.
leprosy. Finally, future work should demonstrate 23. Teles RM, Graeber TG, Krutzik SR, et al. Type I interferon suppresses type II
whether M. lepromatosis is indeed a new species && interferon-triggered human antimycobacterial responses. Science 2013;
339:1448–1453.
causing leprosy. This study suggests that the relative expression of IFNs at the site of infection
determines the outcome of the host response in leprosy.
24. Moller HJ, Peterslund NA, Graversen JH, Moestrup SK. Identification of the
hemoglobin scavenger receptor/CD163 as a natural soluble protein in
Acknowledgements plasma. Blood 2002; 99:378–380.
25. Moura DF, de Mattos KA, Amadeu TP, et al. CD163 favors Mycobacterium
Funding source: Hospital and Homes of St Giles. leprae survival and persistence by promoting anti-inflammatory pathways in
lepromatous macrophages. Eur J Immunol 2012; 42:2925–2936.
26. Ogasawara N, Oguro T, Sakabe T, et al. Hemoglobin induces the expression
Conflicts of interest of indoleamine 2,3-dioxygenase in dendritic cells through the activation of
PI3K, PKC, and NF-kappaB and the generation of reactive oxygen species.
There are no conflicts of interest J Cell Biochem 2009; 108:716–725.

418 www.co-infectiousdiseases.com Volume 26  Number 5  October 2013

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 New findings in the pathogenesis of leprosy Polycarpou et al.

27. de Souza Sales J, Lara FA, Amadeu TP, et al. The role of indoleamine 2, 3- 39. da Motta-Passos I, Malheiro A, Gomes Naveca F, et al. Decreased RNA
dioxygenase in lepromatous leprosy immunosuppression. Clin Exp Immunol expression of interleukin 17A in skin of leprosy. Eur J Dermatol 2012;
2011; 165:251–263. 22:488–494.
28. Schenk M, Krutzik SR, Sieling PA, et al. NOD2 triggers an interleukin-32- 40. Kawaguchi M, Kokubu F, Huang SK, et al. The IL-17F signaling pathway is
& dependent human dendritic cell program in leprosy. Nat Med 2012; 18:555– involved in the induction of IFN-gamma-inducible protein 10 in bronchial
563. epithelial cells. J Allergy Clin Immunol 2007; 119:1408–1414.
This study shows that expression of NOD2 and IL-32 at the site of leprosy infection 41. Khader SA, Gopal R. IL-17 in protective immunity to intracellular pathogens.
is greater in patients with limited as compared to progressive leprosy. Virulence 2010; 1:423–427.
29. Chung AW, Sieling PA, Schenk M, et al. Galectin-3 regulates the innate 42. Chaitanya S, Lavania M, Turankar RP, et al. Increased serum circulatory levels
& immune response of human monocytes. J Infect Dis 2013; 207:947–956. of interleukin 17F in type 1 reactions of leprosy. J Clin Immunol 2012;
This study shows that expression of galectin-3 is associated with lepromatous 32:1415–1420.
leprosy. 43. Zenha EM, Wambier CG, Novelino AL, et al. Clinical and immunological
30. Cogen AL, Walker SL, Roberts CH, et al. Human beta-defensin 3 is up- evaluation after BCG-id vaccine in leprosy patients in a 5-year follow-up study.
& regulated in cutaneous leprosy type 1 reactions. PLoS Negl Trop Dis 2012; J Inflamm Res 2012; 5:125–135.
6:e1869. 44. Martiniuk F, Giovinazzo J, Tan AU, et al. Lessons of leprosy: the emergence of
This is the first study that shows upregulation of b-defensin 3 by M. leprae in TH17 cytokines during type II reactions (ENL) is teaching us about T-cell
keratinocytes but not in macrophages and leads to future work on the interactions plasticity. J Drugs Dermatol 2012; 11:626–630.
between keratinocytes and M. leprae. 45. Desvignes L, Ernst JD. Interferon-gamma-responsive nonhematopoietic cells
31. Walker SL, Roberts CH, Atkinson SE, et al. The effect of systemic corticos- regulate the immune response to Mycobacterium tuberculosis. Immunity
teroid therapy on the expression of toll-like receptor 2 and toll-like receptor 4 2009; 31:974–985.
in the cutaneous lesions of leprosy Type 1 reactions. Br J Dermatol 2012; 46. Han XY, Seo YH, Sizer KC, et al. A new Mycobacterium species causing
167:29–35. diffuse lepromatous leprosy. Am J Clin Pathol 2008; 130:856–864.
32. Kaplan G, Weinstein DE, Steinman RM, et al. An analysis of in vitro T cell 47. Han XY, Sizer KC, Thompson EJ, et al. Comparative sequence analysis of
responsiveness in lepromatous leprosy. J Exp Med 1985; 162:917–929. Mycobacterium leprae and the new leprosy-causing Mycobacterium lepro-
33. Laal S, Sharma YD, Prasad HK, et al. Recombinant fusion protein identified by matosis. J Bacteriol 2009; 191:6067–6074.
lepromatous sera mimics native Mycobacterium leprae in T-cell responses 48. Vera-Cabrera L, Escalante-Fuentes WG, Gomez-Flores M, et al. Case of
across the leprosy spectrum. Proc Natl Acad Sci U S A 1991; 88:1054–1058. diffuse lepromatous leprosy associated with ‘Mycobacterium lepromatosis’. J
34. Chaduvula M, Murtaza A, Misra N, et al. Lsr2 peptides of Mycobacterium Clin Microbiol 2011; 49:4366–4368.
leprae show hierarchical responses in lymphoproliferative assays, with se-
49. Yang Han X, Clement Sizer K, Tan HH. Identification of the leprosy agent
lective recognition by patients with anergic lepromatous leprosy. Infect Immun
Mycobacterium lepromatosis in Singapore. J Drugs Dermatol 2012; 11:168–
2012; 80:742–752.
172.
35. Saini C, Prasad HK, Rani R, et al. Lsr2 of Mycobacterium leprae and its
synthetic peptides elicit restitution of T cell responses in erythema nodosum 50. Jessamine PG, Desjardins M, Gillis T, et al. Leprosy-like illness in a patient with
leprosum and reversal reactions in patients with lepromatous leprosy. Clin Mycobacterium lepromatosis from Ontario, Canada. J Drugs Dermatol 2012;
Vaccine Immunol 2013; 20:673–682. 11:229–233.
36. Palermo ML, Pagliari C, Trindade MA, et al. Increased expression of regulatory 51. Han XY, Sizer KC, Velarde-Felix JS, et al. The leprosy agents Mycobacterium
T cells and down-regulatory molecules in lepromatous leprosy. Am J Trop Med lepromatosis and Mycobacterium leprae in Mexico. Int J Dermatol 2012;
Hyg 2012; 86:878–883. 51:952–959.
37. Attia EA, Abdallah M, Saad AA, et al. Circulating CD4þ CD25 high FoxP3þ T 52. Han XY, Jessurun J. Severe leprosy reactions due to Mycobacterium lepro-
cells vary in different clinical forms of leprosy. Int J Dermatol 2010; 49:1152– matosis. Am J Med Sci 2013; 345:65–69.
1158. 53. Gillis TP, Scollard DM, Lockwood DN. What is the evidence that the putative
38. Miossec P. IL-17 and Th17 cells in human inflammatory diseases. Microbes Mycobacterium lepromatosis species causes diffuse lepromatous leprosy?
Infect 2009; 11:625–630. Lepr Rev 2011; 82:205–209.

0951-7375 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-infectiousdiseases.com 419

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.