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Lecture 17: Attack by Complementand Counterattack by Microbes
Lecture 17: Attack by Complementand Counterattack by Microbes
2
Review Concepts of Complement
Complement was addressed in Lecture 3
Major first line of defense (innate immunity)
Major functions:OpsonizationCell LysisActivation of phagocytic cells
3
Overview of Complement
4
Complement as an Important Bridge
Ricklin, Lambis (2007)Nature Biotech 25:1265.
5
Complement Evasion - General
6
Recognition of Conserved Cell wall Features
TLR4
TLR2
Loose unstructured network of polysaccharidesProtects against phagocytosis
Aids in adherenceInhibits complement activation through binding of factor H
Gram-
7
Evasion of Toll-like Receptors (TLR)
Pathogens can modify targets of innate immunity
The gram-negative bacteria Salmonella and Yersinia can change theirLPS structure, making it less stimulatory for TLR4.
Many pathogens down-regulate their flagellin genes upon entry into thehost. This prevents recognition by TLR5.
LPS - lipopolysaccharide, abundant molecules in most Gram-
8
Streptococcus pneumoniae produces>100 types of capsular polysaccharide
9
Complement: Added Features - Lambris, 2008
10
Complement Pathways
Complement Activation
Proteins are normally inactive -need to be activated (or transient)
Activation - sequential proteolysis
Covalent Attachment - becomestably active after attaching tomicrobe (ab complexes)
Regulation! - important tominimize complement mediateddamage to host cells
11
ComplementRegulation
Regulators of ComplementActivation (RCA)
Proteins that regulate complementStructurally similar proteins
Complement receptor 1 (CR1)Factor H (fH)C4-binding protein (C4BP)Decay accelerating factor (DAF)
12
Complement Regulation - Complexity
Normal conditions
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Complement Activation Regulators
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C1 Inhibitor Regulation
15
Inhibition of C3 Convertase Formation
16
Factor I mediated cleavage of C3b
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Complement: Added Features - Lambris, 2008
18
Mechanisms of Complement Evasion
Three main strategies addressed in review
Making use of the host’s arsenal - acquiring regulatorsadaptations by binding RCA that circulateRCA are the natural regulatorsRecruitment and mimicry
Cutting through complement - pathogen proteases
Direct interventions - microbial complement inhibitors
19
Complement Evasion (Lambris, 2008)
20
Factor H as a Complement Regulator
What is Factor H?
150 kDa glycoproteinCirculates in plasma (0.5 - 0.8 mM concentration)Central role in regulating Alternative Pathway
How does Factor H regulate complement?binds to complement factor-3b, making inactivated complement factor-3b(iC3b) susceptible to cleavage by complement factor I, and by interferingwith the binding of properdin factor B (complement factor B) tocomplement factor C3b
21
Factor H in Complement Regulation
Amplification of complement activation
25
Mechanisms of Complement Evasion
Three main strategies addressed in review
Making use of the host’s arsenal
Cutting through complementpathogen proteases (almost exclusively bacteria)
Direct interventions - microbial complement inhibitors
26
Complement Evasion (Lambris, 2008)
27
Complement Evasion - Proteases
Examples:all these proteases cleave C1qPseudomonas spp. Alkaline protease (PaAP) elastase (PaE)Porphyromonas spp. - PrtH
These proteases are also capable ofcleaving Ig molecules!
End result: prevents activation ofclassical pathway
28
Complement Evasion - Proteases
Examples:all these proteases cleave C3Pseudomonas spp. Alkaline protease (PaAP) elastase (PaE)
Porphyromonas spp. - PrtH
End result: inactivation of C3 bycleavage into non-functional
subunits different from C3a and C3b
29
Complement Evasion - Proteases
Examples:all these proteases cleave C5aSerratia marcescens 56 kDa protease (no formal name)
Streptococcus spp. scpA scpB
End result: disassembles the pro-inflammatory signaling cascade
30
Mechanisms of Complement Evasion
Three main strategies addressed in review
Making use of the host’s arsenal
Cutting through complement
Direct interventionsmicrobial complement inhibitorsdestabilize complement efficiencyonly a few direct inhibitor have been identifiedmost characterized from Staphylococcus aureus
31
Complement Evasion - Direct Inhibition
Examples:
Borrelia burgdorferi CD-59 like protein (binds C9, C8)
Streptococcal spp. SIC (streptococcal inhibitor ofcomplement)
Schistosoma spp. Paramyosin (binds C9, C8)
End result: able to inhibit MACformation
32
Complement Evasion - Direct Inhibition
Examples:Complement C2 receptor trispanning(CRIT)
Trypanosoma spp. CRIT
Schistosoma spp. CRIT
End result: disrupts interactionbetween C2 and C4 prevent CP
convertase formation