Inhibition of Complement Activation by a SecretedStaphylococcus aureusProtein

Abstract

Staphylococcus aureus can cause a variety of acute and chronic diseases. The ability of S. aureus to cause persistent infections has been linked to its ability to evade or inactivate host immune responses. We have identified a secreted 19-kDa protein produced by S. aureus that binds to the complement protein C3. N-terminal sequencing of this protein identified it as the extracellular fibrinogen-binding protein (Efb). In this study, we demonstrate that Efb can bind to the alpha -chain of C3 and inhibit both the classical and alternative pathways of complement activation. In addition, we show that Efb can inhibit complement-mediated opsonophagocytosis in a dose-dependent manner and that Efb inhibits complement activity by blocking deposition of C3 or by preventing further complement activation beyond C3b. These data suggest that Efb is a virulence factor involved in facilitating persistent S. aureus infections by interfering with complement activity in vivo.

Host Airway Proteins Interact withStaphylococcus aureusduring Early Pneumonia

“…Interestingly the S. aureus receptors for complement C3 and Igs, Efb, and protein A, respectively, have antiopsonic properties. The extracellular fibrinogen binding protein Efb inhibits opsonophagocytosis by binding complement C3, thus preventing complement C3 from opsonizing the bacteria (29). Protein A is the most abundant protein on the surfaces of S. aureus cells and has been shown to be critical for the survival of S. aureus in the airway (12,26,47).…”

Identification and Characterization of the C3 Binding Domain of the Staphylococcus aureus Extracellular Fibrinogen-binding Protein (Efb)

“…The ability of S. aureus to affect such diverse tissues and cause persistent infections is in part related to their ability to manipulate or evade multiple defense mechanisms (1,(12)(13)(14)(15)(16)(17). Pathogens associated with persistent infections often produce multiple microbial immunomodulatory molecules (12,17) to counter the immune systems of the host (i.e.…”

“…Pathogens associated with persistent infections often produce multiple microbial immunomodulatory molecules (12,17) to counter the immune systems of the host (i.e. adaptive and innate immunity) (12,17), and this strategy results in the effective avoidance or delay of the pathogen clearance while concomitantly affecting the development of a protective memory response. Well characterized members of the S. aureus microbial immunomodulatory molecule family of proteins are the super antigens and protein A, which can affect T cell and antibody responses, respectively (1).…”

“…Well characterized members of the S. aureus microbial immunomodulatory molecule family of proteins are the super antigens and protein A, which can affect T cell and antibody responses, respectively (1). Recent additions to this rapidly growing protein family are the secreted extracellular fibrinogen-binding protein (Efb) 1 (18 -23), which we identified as an inhibitor of various complement-mediated processes (17), the major histocompatibility complex class II analog protein (Map), which interferes with T cell function and neutrophil migration (12,24), and the chemotaxis inhibitory protein from S. aureus (CHIPS) (13,25), which interferes with the inflammatory response early in the infection process by binding to the C5a-and formylated peptide receptors.…”

“…Many successful human pathogens have evolved either direct C3 inactivation strategies by producing C3-binding proteins (e.g. S. aureus, Trypanosoma cruzi, and Pseudomonas aeruginosa) (17,(32)(33)(34) or indirect mechanisms by targeting and manipulating the host endogenous C3-inhibitor, Factor H (or Factor H-like proteins) (e.g. Borrelia burgdorferi, Candida albicans, and Streptococcus pyogenes) (35)(36)(37)(38).…”