Pathogens have evolved diverse mechanisms for evading the complement system. Some microbes express thick cell walls that prevent the binding of complement proteins, such as the MAC. Gram-positive bacteria and some fungi are examples of microbes that use this relatively nonspecific evasion strategy. A few of the more specific mechanisms used by selected pathogens will be considered here. These evasion mechanisms may be divided into three groups.
• Microbes can evade the complement system by recruiting host complement regulatory proteins. Many pathogens, in contrast to nonpathogenic microbes, express sialic acids, which can inhibit the alternative pathway of complement by recruiting Factor H, which displaces C3b from Bb. Some pathogens, like schistosomes, N. gonorrhoeae, and certain Haemophilus species, scavenge sialic acids from the host and enzymatically transfer the sugar to their cell surfaces. Others, including Escherichia coli K1 and some meningococci, have evolved special biosynthetic routes for sialic acid generation. Some microbes synthesize proteins that can recruit the regulatory protein Factor H to the cell surface. GP41 on human immunodeficiency virus (HIV) can bind to Factor H, and this property of the virus is believed to contribute to virion protection. Many other pathogens have evolved proteins that facilitate the recruitment of Factor H to their cell walls. These include bacteria such as Streptococcus pyogenes; Borrelia burgdorferi (the causative agent of Lyme disease); N. gonorrhoeae, N. meningitidis; the fungal pathogen Candida albicans; and nematodes, such as Echinococcus granulosus. Other microbes, such as human immunodeficiency virus (HIV), incorporate multiple host regulatory proteins into their envelopes. For instance, HIV incorporates the GPI-anchored complement regulatory proteins DAF and CD59 when it buds from an infected cell.
• A number of pathogens produce specific proteins that inhibit different steps in complement activation. E. coli makes a C1q-binding protein that inhibits the formation of a complex between C1q, C1r, and C1s. Staphylococcus aureus makes a protein called staphylococcal complement inhibitor that binds to and stably inhibits both the classical and alternative pathway C3 convertases and thus inhibits all three complement pathways. Glycoprotein C-1 of the herpes simplex virus destabilizes the alternative pathway convertase by preventing its C3b component from binding to proper din. GP160, a membrane protein on Trypanosoma cruzi, the causative agent of Chagas disease, binds to C3b and prevents the formation of the C3 convertase and also accelerates its decay. VCP-1 (vaccinia virus complement inhibitory protein 1), a protein made by the vaccinia virus, structurally resembles human C4BP but can bind to both C4b and C3b and accelerate the decay of both C3 and C5 convertases.
• Complement-mediated inflammation can also be inhibited by microbial gene products. S. aureus synthesizes a protein called chemokine inhibitory protein of staphylococci, which is an antagonist of the C5a anaphylatoxin.
