Bacterial persistence in the host: immune

evasion
Anti-Immune Strategies of Bacteria
Secreted modulators or toxins toxins
proteases
Modulators on the - Lipid A of LPS
pathogen surface - carbohydrates such as capsules
- outer membrane proteins
- adhesins and invasins
Hide from immune surveillance - avoid phagolysosomal fusion
- inhibit phagocytosis
Antigenic hypervariability - vary many surface structures
- pili, outer membrane proteins, LPS
- strain to strain variation
Subvert or kill immune - superantigens
cells/phagocytes - avoid phagolysosomal fusion
- block inflammatory pathways by
injecting effectors
- replicate within and overrun immune
cells
Block acquired immunity - IgA proteases
- block antigen presentation
Inhibit complement - proteases to degrade complement
- produce capsules and long chain LPS
to avoid complement deposition and MAC attack
Inhibit cytokines/ - block inflammatory pathways
interferon/chemokines - activate alternate pathways
- secrete proteases to degrade
Modulate - inhibit apoptosis
apoptosis/autophagy - activate death signaling pathways
- alter apoptotic sigaling pathways
Interfere with TLRs - alter TLR ligands to decrease recognition
- bind to TLR to dampen inflammation
- inject effectors to inhibit downstream
inflammation signaling
Block antimicrobial - secrete proteases to degrade
small molecules - alter cell surface to avoid peptide insertion
- use pumps to transport peptide
- directly sense small molecules to trigger
defense mechanisms
Block intrinsic cellular - alter ubiquitin pathway
pathways - alter transcriptional programs
 Bacterial surface structures and immune
evasion
Capsule: used by most extracellular bacterial pathogens that
circulate systemically within the body (eg, S. Pneumoniae, H.
influenzae, E. coli K1, N. meningitidis etc)
 Masks antigenic surface structures like O-Ag or PAMPs
Blocks complement activation by complexing with LPS O-Ag
Helps to evade phagocytosis by masking opsonins on the cell
surface and making opsonic ligands inaccessible to phagocytes
Confer antigenic variation – phase variation of Gr. B
streptococcus and B. fragilis
Protect from antimicrobial peptides - Anionic capsules are
released in presence of AMPs and bind them, reducing the
amount of peptides reaching the bacterial surface
Helps penetration through a paracellular route - S. pyogenes
hyaluronic acid capsule binds to CD44 on the pharyngeal or skin
epithelial cell surface
LPS modification and immune evasion
LPS is surface exposed and a target of complement, but
protrudes from the surface, so membrane insertion by
MAC does not occur
• Avoidance of Immune Surveillance
1. Lipid A modification to decrease TLR4 response –
Hypoacylation (H. pylorie, shigella) or hyperacylation (K.
pneuminiae);
2. Salmonella PagL (deacylase) and PagP
(palmitoyltransferase);

• By dampening immune responses

P. gingivalis lipd A – both agonist and antagonist of
TLR2 and 4
 COMPLEMENT EVASION
• recruitment of C regulators
• Degradation of C factors or inhibition of proteolytic
complex formation
 Bacterial perturbation of cytokine synthesis
Suppression of cytokine synthesis

Organism Cytokines suppressed

Actinomyces IL-2, IL-4, IL-5, and IFN-g from CD4+ cells
Escherichia coli IL-2, IL-4, IL-5, and IFN-g from PBMCs
Yersinia enterocolitica TNF-a from LPS-stimulated murine
macrophages
Vibrio cholerae TNF-a release from peritoneal mast cells
Bacillus anthracis TNF-a by LPS-stimulated human monocytes
Pseudomonas IL-1a, IL-1b, TNF-a, and IFN-g by human
aeruginosa monocytes
Salmonella typhimurium IL-2 by murine T lymphocytes
Cytokine degradation

Organism Cytokines Enzyme

degraded resposible
Pseudomonas aeruginosa IL-2, TNF-a, IFN-g Alkaline protease,
elastase
Legionella pneumophila IL-2 Zn-
metalloproteinase
Porphyromonas gingivalis IL-1b, IL-6, IL-1ra Gingipain
Cytokine binding and bacterial growth stimulation

Organism Cytokines bound

E. coli, S. typhimurium, TNF-a,
Shigella flexneri
E. coli IL-1b, IL-2, GM-
CSF
M. tuberculosis TGF-b, EGF
Listeria monocytogenes CSF-1, IL-3
Bacterial evasion of host antimicrobial
peptides

S. aureus S. aureus
L. monocytogenes P. aeruginosa
Streptococci Streptococci
M. tuberculosis
P. aeruginosa
N. meningitidis
H. pylori
Neisseria spp
Salmonella spp.
Legionella pneumophila
Haemophilus influenzae
Bacterial evasion of host antimicrobial
peptides

Neisseria gonorrhoeae P. Aeruginosa

N. Meningitidis S. aureus
S. Typhimurium Escherichia coli
S. aureus Group A Streptococcus
S. Typhimurium
Porphyromonas gingivalis
Bacterial evasion of host antimicrobial
peptides

S. Typhimurium Shigella dysenteriae

P. aeruginosa Shigella flexneri
L. monocytogenes S. Typhimurium
Neisseria gonorrhoeae
P. aeruginosa
 Activation of inhibitory signaling
N. Meningitis
a. GBS
Staph
 Bacterial Acid resistance

EHEC
Three types of AR systems:
• AR system 1(glucose-repressed or oxidative)
• AR system 2 (glutamate-dependent)
• AR system 3 (arginine-dependent).
Bacterial evasion of recognition by the host

H. pylori
Inhibition of host innate immune signaling
 Metallo proteasec Serine protease
Cysteine protease

Metallo proteasec

Serine protease
inhibition of adaptive immune response (H. pylori)
inhibition of adaptive immune response (Shigella)
 Phagocyte receptors

Opsonic receptors
• FcγRI (CD64) IgG1 = IgG3 > IgG4
• FcαRI (CD89) IgA,
• FcεRI IgE
• CR1 (CD35) MBL, C1q, C4b, C3b
• CR3 (αMβ2, CD11b/CD18, Mac1) iC3b, β-
Integrin α5β1 Fibronectin, vitronectin
PRRs (non-opsonic)
• Mannose receptor (CD206) Mannan
• Dectin-1 (CLEC7A) β-1,3-Glucan
• CD14 Lipopolysaccharide-binding protein
• SR-A (CD204) LPS, LTA
• CD36 P. falciparum-infected RBC
• MARCO Bacteria
Phagosomee maturation
 Phagolysosome

Highly acidic (pH 4.5) due to insertion of additional V-ATPases

Characterized by: less MVBs, less LBPA and PI-3P, elevated mature
cathepsin and lack of mannose-6P receptors (compared to late
phagosome)
Microbicidal activities of phagocytes

x PGL

(cathepsin) x peptidoglycan
Antimicrobial proteins and peptides

(Fe scavenger)
(Fe2+, Zn2+, Mn2+)
(Recruited to phagosomal mem after bact uptake)
 Bacterial resistance to phagocytic killing
• Interference with phagocytosis:
Scavenging, inhibiting or degrading opsonic Abs or complement
Directly impairing phagocytic machinery
• Counteracting acid accumulation or acquiring acid resistant proteins
• Degradation of AMPs
• Expression of catalae that neutralizes ROS and/or RNS
• Overcoming iron scarcity by secreting iron scavenging siderophores or
expressing iron storage and transport proteins
• Mounting stress response to dispose of and replace damaged proteins.

A select group of bacteria are ‘professional intracellular pathogens

They survive and replicate within phagocytes
Have developed multiple strategies to perturb phagosomal maturation
(arresting and reprogramming maturation, escaping maturing
phagosomes or withstanding microbicidal properties of
phagolysosomes)
Inhibition of phagosome maturation
Resistance to phagolysosme
Resistance to phagolysosme
Legionella pneumophilia: reprogramming phagosomal maturation
•Phagocytosis by macrophage is thr’ CRs: formation of LCVs
•Internalized Legionella modulqtes LCV maturation by
avoiding default endolysosomal pathway.
•Instead, ER-derived secretory vesicles fuse with LCV using
host Rab1 and Arf1 thr’ T4SS effectors (DrrA, LidA, RalF).
Coxiella burnetti: reprogramming phagosomal maturation

•Resides in acidified lysosome-like compartment and

replicates in the presence of antimicrobial factors

•Phase 1 (small cell) variant (virulent) is

phagocytosed by binding to integrin αVβ3 followed by
activation of signaling pathways that cause actin
polymerization, propelling internalization and
formation of vacuole.

•Phase 2 (large cell) variant (avirulent) does not

induce cell signaling

•Autopagic protein LC3 recruited to Coxiella

phagosome delays its fusion with lysosome

•Replicative Coxiella vacuole (pH~4.8) is formed

within 48 hrs

•SOS DNA repair system protects from chromosomal

damage by ROS