Chapter 6 : Complement in Infections

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The complement system provides a fundamental component of the body's immune response to invading microorganisms. This chapter highlights the various roles of the complement system in the orchestration of the immune response towards microbial infections, gives examples of microbial strategies to evade complement-mediated clearance, and discusses how acquired and inherited complement deficiencies may predispose an organism to infectious disease. Complement is activated by three pathways: the classical pathway, the alternative pathway, and the lectin pathway. The lectin pathway is activated by carbohydrate recognition molecules that bind to polysaccharide on the surface of a pathogen. Factor B, factor D, and properdin (factor P) are specific components of the alternative pathway of complement activation. The complement activation is tightly regulated by membrane-bound and fluid-phase regulatory components to avoid runaway activation of the enzymatic cascade that could lead to excess host tissue damage, inflammation, and depletion of complement components. A deficiency in any component of the classical pathway is associated with an increased risk of immunological disease and recurrent bacterial infections. Pneumolysin is a potent virulence factor produced by all serotypes of . Pneumolysin is released as a 52 kDa soluble monomer. It binds cholesterol-containing membranes and the monomeric subunits oligomerize to form a pore in the target cell membrane that leads to cell death. Pneumococcal surface protein C (PspC) is a major virulence factor of and contributes to many different biological functions.

Citation: Schwaeble W, Ali Y, Lynch N, Wallis R. 2011. Complement in Infections, p 85-95. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch6
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Image of FIGURE 1

A simplified diagram of the three complement activation pathways: the classical, the lectin pathway, and the alternative pathway. Both the classical and the lectin pathway share the identical C3 and C5 convertase complexes formed after cleavage of C4 by either activated C1s (classical pathway) or activated MASP-2 (lectin pathway) (see 1) and subsequent cleavage and activation of C4b-bound C2 through activated C1s or MASP-2 (see 2). Activation of the alternative pathway is tightly controlled by membrane associated complement regulatory components and the competition of the main fluid phase antagonists factor B and factor H for binding C3b or hydrolsed C3. The affinity of factor B to bind C3b is higher on “activating “surfaces, and the half-life of C3bB, C3Bb, and C3Bb(C3b)n complexes, significantly increased by the action of properdin, allows the alternative pathway amplification loop to be formed. The alternative pathway activation loop allows C3b to be used to (i) generate more alternative pathway C3 convertases and (ii) maximize complement opsonization of activating (microbial) surfaces, or (iii) switch substrate specificity of the C3 convertases to cleave C5 through deposition of multiple C3b molecules in close proximity. This flow diagram summarizes the synergisms between the three activation pathways and points out that the initial C3b required for the alternative pathway activation loop to form can either be provided via the classical or the lectin pathway, or via spontaneous hydrolysis of C3 (C3(HO), which, like C3b, can bind to factor B in the absence of activation of the latter two pathways.

Citation: Schwaeble W, Ali Y, Lynch N, Wallis R. 2011. Complement in Infections, p 85-95. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch6
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Image of FIGURE 2

Structure of the classical and lectin pathway recognition components. The basic subunits are trimers, with N-terminal collagen-like and C-terminal globular domains. In C1q, the subunit is a heterotrimer of C1qA-, B-, and C-chains and the globular heads are antibody Fc binding domains. For MBL and the ficolins, the subunits are homotrimers and the globular domains are C-type lectin and fibrinogen-like domains, respectively. Subunits assemble, via their collagenous domains into higher order oligomers, typically trimers and tetramers for MBL and the ficolins, and hexamers for C1q.

Citation: Schwaeble W, Ali Y, Lynch N, Wallis R. 2011. Complement in Infections, p 85-95. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch6
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Regulatory components of complement activation and their known interaction with pathogens

Citation: Schwaeble W, Ali Y, Lynch N, Wallis R. 2011. Complement in Infections, p 85-95. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch6

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