Lecture 17: Attack by Complementand Counterattack by Microbes

Lecture 17: Attack by Complementand Counterattack by Microbes

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Review Concepts of Complement

Complement was addressed in Lecture 3

Major first line of defense (innate immunity)

Major functions:OpsonizationCell LysisActivation of phagocytic cells

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Overview of Complement

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Complement as an Important Bridge

Ricklin, Lambis (2007)Nature Biotech 25:1265.

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Complement Evasion - General

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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-

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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-

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Streptococcus pneumoniae produces>100 types of capsular polysaccharide

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Complement: Added Features - Lambris, 2008

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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

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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)

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Complement Regulation - Complexity

Normal conditions

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Complement Activation Regulators

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C1 Inhibitor Regulation

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Inhibition of C3 Convertase Formation

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Factor I mediated cleavage of C3b

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Complement: Added Features - Lambris, 2008

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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

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Complement Evasion (Lambris, 2008)

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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

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Factor H in Complement Regulation

Amplification of complement activation

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Role of Factor H

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Pathogen proteins that bind complement

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Evading Complement Regulation

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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

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Complement Evasion (Lambris, 2008)

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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

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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

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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

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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

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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

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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