Complement inhibition by gram-positive pathogens: molecular mechanisms and therapeutic implications

Abstract

The plasma proteins of the complement system are essential in the innate immune response against bacteria. Complement labels bacteria with opsonins to support phagocytosis and generates chemoattractants to attract phagocytes to the site of infection. In turn, bacterial human pathogens have evolved different strategies to specifically impair the complement response. Here, we review the large arsenal of complement inhibitors produced by the gram-positive pathogens Staphylococcus aureus and Group A Streptococcus. We discuss how these bacterial molecules provide us with new tools to treat both infectious and inflammatory disease conditions in humans.

Fig. 1

Schematic overview of the complement system. The complement cascade is activated by recognition of microbe-bound antibodies or microbial sugars by the C1 complex (CP) or the MBL- and ficolin-MASP-2 complex (LP), respectively. Both C1s and MASP-2 cleave complement proteins C4 and C2 to generate the CP/LP C3 convertase: C4b2a. The Alternative Pathway (AP) C3 convertase C3bBb is generated after binding of fB to surface-bound C3b and subsequent cleavage by fD. The AP C3 convertase is stabilized by the positive regulator human properdin [47, 48]. Both C3 convertases (C4b2a and C3bBb) cleave C3 into C3a and C3b. C3b covalently binds to bacterial surfaces, thereby amplifying complement activation through formation of new C3 convertases and contributes to phagocytosis, antigen presentation, and formation of C5 convertases (C4b2a3b and C3bBb3b). C5 convertases cleave C5 into the anaphylatoxin C5a, which attracts neutrophils to the site of infection, and C5b, which forms a complex with complement proteins C6–C9 to generate the membrane attack complex

Fig. 2

Bacterial evasion of complement recognition (a) and opsonization (b). Illustrated are proteins of S. aureus (red) and GAS (yellow) that modulate complement recognition and opsonization. a To prevent recognition by the classical pathway, S. aureus expresses the surface proteins ProtA and Sbi. Both proteins bind the Fc tail of IgG preventing its interaction with FcR on neutrophils. Another mechanism to prevent recognition is by inactivating IgG, either directly by proteases IdeS, Mac-2, and SpeB, or indirectly by SAK-activated plasmin. b There are three ways by which S. aureus and GAS modulate opsonization: (1) C3 cleavage; directly by SpeB or indirectly by SAK-mediated activated plasmin ClfA binds human fI, thereby enhancing C3 cleavage. (2) Convertase modulation; S. aureus inactivates the C3 convertases by secreting SCIN, SCIN-B, SCIN-C, Efb, and Ecb. (3) Modulating host regulators; Sbi and the streptococcal M-protein bind the negative convertase regulators (human FH, FHL1, C4BP, and CD46) while SpeB cleaves the positive convertase regulator, properdin

Fig. 3

Bacterial evasion of C5-mediated responses. Illustrated are proteins of S. aureus (red) and GAS (yellow) that modulate C5-mediated responses. Efb and Ecb block the formation of C5 convertases and thereby inhibit C5a and MAC generation. SSL7 binds to C5 and prevents the cleavage of C5 into C5a and C5b. Neutrophil influx and phagocytosis are inhibited by CHIPS, which binds the C5aR, and ScpA that cleaves C5a. SIC inhibits the formation of the MAC, the final step in the complement cascade