a | After activation of the complement system by antibody complexes (classical pathway (CP)), terminal mannose (lectin pathway (LP)) or by spontaneous and induced C3 hydrolysis (alternative pathway (AP)), the C3 convertases cleave C3 to its active fragments C3a and C3b. Covalent binding of C3b (opsonization) amplifies the cascade and mediates phagocytosis and adaptive immune responses by binding to complement receptors (CRs). Accumulation of deposited C3b also leads to the assembly of C5 convertases that activate C5 to C5a and C5b. Whereas C5b initiates the formation of the lytic membrane-attack complex (MAC), the anaphylatoxins C3a and C5a induce pro-inflammatory and chemotactic responses by binding to their receptors (C3aR and C5aR). On pathogenic surfaces, properdin (P) induces and stabilizes the AP C3 convertase, which leads to enhanced complement activity. b | Microorganisms have developed many ways to evade complement actions. Suppression of CP activation can be achieved by trapping endogenous C1 inhibitor (C1-INH) to the surface or by inactivating antibodies through the capture of their Fc regions. Whereas the recruitment of soluble regulators by capturing host proteins is a common strategy to impair downstream complement actions, certain viruses also produce structural mimics of these regulators. In addition, some microbial proteins have similar activities to CD59 in preventing MAC formation. Direct inhibition of C3, the C3 and C5 convertases, C5 or the C5a receptor (C5aR) is a prominent strategy of Staphylococcus aureus. Finally, a set of different microbial proteases can degrade many of the crucial components of the complement system. These proteases act directly or by capturing and activating a human protease. An extended list of complement evasion proteins can be found in Supplementary information S1 (table). Increased and decreased activity is represented by thick and thin arrows, respectively. F, ficolin; fB, factor B; fD, factor D; fI, factor I, MASP, MBL-associated serine protease; MBL, mannose-binding lectin; RCA, regulators of complement activation.

A range of S. aureus proteins that interact with targets from the complement system have been structurally analysed. a | The immunoglobulin G (IgG)-binding module of staphylococcal protein A (SpA; Protein Data Bank (PDB) code: 1BDD63), the C3-binding domain of the extracellular fibrinogen-binding protein (Efb; PDB code: 2GOM74) and staphylococcal complement inhibitor (SCIN; PDB code: 2QFF78) share similar structural motifs, but show differential functionality. b | Both staphylococcal superantigen-like protein-7 (SSL-7; PDB code: 1V1O103) and the chemotaxis inhibitory protein of S. aureus (CHIPS; PDB code: 1XEE104) attenuate complement on the level of C5, but bind to unrelated targets (C5 protein and C5a receptor, respectively). The solution structure of human C5a (obtained by nuclear magnetic resonance at pH 5.2; PDB code: 1KJS105) is shown as a comparison. All protein-structure representations are coloured according to their secondary structure (α-helices in red and β-sheets in yellow).

Certain orthopox viruses and herpes viruses express proteins that closely mimic the structure and function of human regulators of complement activation. This structural similarity is illustrated for vaccinia virus complement-control protein (VCP; Protein Data Bank (PDB) code: 1G40 (REF. 27)) (a) and human decay-accelerating factor (DAF; PDB code: 1OJV102) (b), both of which have four short consensus repeat (SCR) domains. These SCRs (or complement control protein modules) are common structural motifs in complement components (for example, complement receptors and regulators) and other proteins (such as selectins).