Complement:Alternative Pathway by a gycyphosphatidylnosito (P)an- tors are related in structure and domain composition to the Distinet strategies are employed by s to interfere with complement activation. Control capsu C3 rec Whilea powerful amplification isdesirableand required on complement regulators.A number of pathogens and cells and tis ther in general,and bacteria express proteins that restrict C3 activation e part be nity of by control lling C ass d C or by acting as cted f thi svstem.The importance and rlevance ofprotection can be was the identification of a CRl-like molecule in herpe concluded from the large number of regulatory and simplex virus(HSV)type Iand II(Fishelson,1994).Several domain motifs and stru inactivator proteins.which actually exceeds the numbe uctures of the mammalian compl alte proteins R reted microbial comp ment regula otein is the convertases and prevent formation of a new convertase 35-kDa vaccinia virus complement control protein (VCP) binding to C3h they K ally degrad activity).Regulatory proteins that control complement ogy to the chain of C4BP.The activity exist in plasma and also on cell surfaces (Table 2). has decay-accelerating and cofactor activity in the classical and the alternative complemen secrete viral par complement Microbes A third stratey is the acquisition of host regulators to enable bacteria and pathogens to control C3b deposition As an evolutionarily old defence system,the alternative nit the of y formed C3 ent pa ny of the ctivat microbes and pathogens.However,during evolution are not efficient activators of the alternative pathway.In microbes have evolved means to cope with the host particular.the presence of sialic acids and complement immune system and to interfere ve b een shown on Escherichic activity.Increasi organisms.Many pathogens have developed the capacity mediates resistance :to complement-induced lysis.M binds the two regulators they com en onon th defence is envisioned by the fact that several independent M5 protein and.in a bound configuration.the protein evasion mechanisms have evolved and are being used by retains its complement regulatory functions.The two microbes to re strict n and o the mplifica uma binc actena for recon ment activation at distinct levels and step protein,while that of factor His oc ated in the conserved proteins used by pathogens either represent host-like region in the middle of the protein (Zipfel and Skerka antigens encoded within the micr or they 999).Acqu1s11 y proteins acqu epos ne s e an been identified on a functionals wellas a genctic leve istance.Arelated mechanism is being used These proteins are expressed either on the surface of a by viruses,as during the budding process viruses like HIV ogenous regula capture ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net 1 membrane by a glycosylphosphatidylinositol (GPI) an￾chor. Control The alternative complement pathway C3 convertase is the step where the activation cascade becomes amplified. While a powerful amplification is desirable and required on foreign surfaces, self cells and tissues in general, and particularly host cells in the direct vicinity of a pathogen, must be protected from this destructive and harmful system. The importance and relevance of protection can be concluded from the large number of regulatory and inactivator proteins, which actually exceeds the number of effector proteins. Several of the major control proteins act on the stage of alternative pathway C3 convertases formation. These regulators dissociate any preformed convertases and prevent formation of a new convertase (decay-accelerating activity) or, by binding to C3b, they make this protein accessible for the serine protease factor I that proteolytically degrades and inactivates C3b (cofactor activity). Regulatory proteins that control complement activity exist in plasma and also on cell surfaces (Table 2). Microbes As an evolutionarily old defence system, the alternative complement pathway is the major effector mechanism of innate immunity to attack, inactivate and eliminate microbes and pathogens. However, during evolution, microbes have evolved means to cope with the host immune system and to interfere and control complement activity. Increasing evidence indicates that host comple￾ment proteins not only act as mammalian complement regulators, but also are a target for pathogenic micro￾organisms. Many pathogens have developed the capacity to evade the pro-inflammatory and destructive effects since they control alternative complement activation on their surface. The importance of the alternative pathway in host defence is envisioned by the fact that several independent evasion mechanisms have evolved and are being used by microbes to restrict complement deposition and amplifica￾tion on the surface. Similar to the protective mechanisms employed by mammalian cells, pathogens control comple￾ment activation at distinct levels and steps. Regulatory proteins used by pathogens either represent host-like antigens encoded within the microbial genome or they are regulatory proteins acquired from their hosts by absorption. Several microbial proteins and genes have been identified on a functional, as well as a genetic level. These proteins are expressed either on the surface of a pathogen or are released into the medium. Several of these proteins that mimic functions of the endogenous regula￾tors are related in structure and domain composition to the host proteins. Distinct strategies are employed by pathogens to interfere with complement activation. One resistance mechanism is the development of an antiphagocytic capsule that physically prevents the access of C3 receptors presented on the surface of phagocytes to C3b deposited on the cell wall of bacteria. A second strategy is the mimicry of complement regulators. A number of pathogens and bacteria express proteins that restrict C3 activation either by controlling C3 convertase assembly or by acting as cofactors for the cleavage of bound C3b. A first example was the identification of a CR1-like molecule in herpes simplex virus (HSV) type I and II (Fishelson, 1994). Several domain motifs and structures of the mammalian comple￾ment components and regulators are also found in microbial proteins (Rother et al., 1994). One example of a secreted microbial complement regulatory protein is the 35-kDa vaccinia virus complement control protein (VCP), a virally encoded protein that is secreted by cells upon infection with the virus (Kotwal and Moss, 1988). This protein is composed of four SCR domains that share amino acid homology to the a chain of C4BP. The protein has decay-accelerating and cofactor activity in the classical and the alternative complement pathway. By being secreted it can protect viral particles from complement￾mediated attack and can augment viral virulence. A third strategy is the acquisition of host regulators to enable bacteria and pathogens to control C3b deposition. Thus, pathogens limit the number of newly formed C3b molecules in the vicinity of the cell and further inactivate C3b molecules at the cell surface. Gram-positive bacteria are not efficient activators of the alternative pathway. In particular, the presence of sialic acids and complement regulator binding proteins have been shown onEscherichia coli K1, Neisseria meningitidis and Streptococcus pyogenes to be important for complement control. One example is the streptococcal M protein, a major virulence factor that mediates resistance to complement-induced lysis. M protein binds the two human complement regulators factor H and reconectin/FHL-1. In plasma absorption experiments, the reconectin/FHL-1 preferentially binds to M5 protein and, in a bound configuration, the protein retains its complement regulatory functions. The two human regulators bind to different sites of the bacterial protein. The binding site for reconectin/FHL-1 is located within the hypervariable, surface-exposed region of theM5 protein, while that of factor H is located in the conserved region in the middle of the protein (Zipfel and Skerka, 1999). Acquisition of the host regulators downregulates C3 deposition on the streptococcal surface and, thus, explains why the hypervariable region of M proteins is essential for phagocytosis resistance. A related mechanism is being used by viruses, as during the budding process viruses like HIV capture membrane-bound complement regulators of the host cell and incorporate these proteins into the viral Complement: Alternative Pathway ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 7