Microbial subversion of the immune response.

A microbe becomes a pathogen by evading—to a greater or lesser extent—the immune defenses of its host. The mechanisms that have evolved for so doing are legion in number and striking in their diversity and ingenuity. They involve mechanisms to evade recognition by—and mechanisms to subvert the effector mechanisms of—both the innate and the adaptive immune response (see Table 1). All classes of infectious agents from the smallest viruses to helminth worms use these techniques albeit in somewhat different ways. An almost ubiquitous target for these subversion mechanisms is the complement system and it is with the subversion of complement by smallpox virus that the report in this issue of PNAS by Rosengard et al. (1) is concerned. An extremely simplified view of the complement system is shown in Fig. 1. There are two principal biologically important steps. The first is brought about by the activation (and subsequent fixation) of C3 by C3-converting enzymes. This step generates the bound C3 fragments (C3b and iC3b) that interact with complement receptors on inflammatory cells and the activation fragments C3a and C5a, which also activate inflammatory cells. The second important step is the formation of the membrane attack complex, which inserts a channel into cell membranes. Regulation of the C3 activation step is achieved by a series of proteins of highly homologous structure that are composed of oligomers of the so-called ‘‘short consensus repeat’’ (SCR) protein domain and are coded in the genome at a single large locus on chromosome 1q. They are known as complement control proteins (CCPs). These include secreted plasma proteins (Factor H and C4-binding protein) and membrane-bound proteins [Membrane cofactor protein (CD46), the complement receptors 1(CD35) and 2(CD21), and decay accelerating factor (CD55)], the last named having a glycolipid anchor. They have two principal activities. They act as cofactors for the proteolytic cleavage by Factor I of C3b to iC3b and (for CR1) from iC3b to C3c and C3dg; and they have ‘‘decay accelerating’’ activity on the C3converting enzymes of both the classical and the alternative complement pathways. Some bacteria can bind Factor H and C4-binding protein to their surfaces where they act as a form of membrane-bound CCP. Viruses have at their disposal the protein-synthesizing apparatus of the host and can make use of this to synthesize homologues of the host CCPs to protect themselves from host complement. Vaccinia virus has a CCP composed of four SCRs, which is known as VCP, and has been extensively studied particularly by Kotwal and Moss and their colleagues (2, 3). Rosengard et al. (1) have now performed the ingenious experiment of synthesizing the corresponding protein of variola—the smallpox virus—and investigating how its properties differ from that of the vaccinia protein. The synthesis was achieved by introducing into the vaccinia protein the 11 amino acid substitutions that are all that distinguish the vaccinia and the variola complement control proteins (which show amino acid sequence homology of around 95%). The variola complement control protein— called SPICE by the authors—shows important differences in its properties from its vaccinia counterpart. It shows a substantially greater degree of specificity for human complement and is 100-fold more active in inactivating human C3b. These findings are of considerable interest in at least two separate contexts.