Fibrin(ogen) engagement of S. aureus promotes the host antimicrobial response and suppression of microbe dissemination following peritoneal infection

Author summaryThe Gram-positive bacterium Staphylococcus aureus (S. aureus) produces a number of soluble and surface-associated proteins that bind the host coagulation protein fibrinogen. The contribution of fibrinogen-S. aureus binding through the fibrinogen receptor clumping factor A (ClfA) in peritoneal infection has not been defined. Elimination of the binding motif on fibrinogen for ClfA or deletion of ClfA from S. aureus significantly reduced S. aureus-fibrinogen binding and bacterial clumping in solution. In a mouse model of peritonitis, loss of these activities resulted in diminished bacterial killing, increased bacterial dissemination, and worsened host survival. Although fibrin polymer formation and fibrin(ogen)-macrophage binding are mechanistically linked to the local antimicrobial response, fibrin formation in and of itself is not sufficient to suppress microbe dissemination. These discoveries have identified important components of the fibrin(ogen)-dependent host antimicrobial response against S. aureus, providing further understanding of this physiological response to infection which could uncover potential therapeutic strategies for peritonitis patients. The blood-clotting protein fibrin(ogen) plays a critical role in host defense against invading pathogens, particularly against peritoneal infection by the Gram-positive microbe Staphylococcus aureus. Here, we tested the hypothesis that direct binding between fibrin(ogen) and S. aureus is a component of the primary host antimicrobial response mechanism and prevention of secondary microbe dissemination from the peritoneal cavity. To establish a model system, we showed that fibrinogen isolated from Fib gamma(Delta 5) mice, which express a mutant form lacking the final 5 amino acids of the fibrinogen gamma chain (termed fibrinogen gamma(Delta 5)), did not support S. aureus adherence when immobilized and clumping when in suspension. In contrast, purified wildtype fibrinogen supported robust adhesion and clumping that was largely dependent on S. aureus expression of the receptor clumping factor A (ClfA). Following peritoneal infection with S. aureus USA300, Fib gamma(Delta 5) mice displayed worse survival compared to WT mice coupled to reduced bacterial killing within the peritoneal cavity and increased dissemination of the microbes into circulation and distant organs. The failure of acute bacterial killing, but not enhanced dissemination, was partially recapitulated by mice infected with S. aureus USA300 lacking ClfA. Fibrin polymer formation and coagulation transglutaminase Factor XIII each contributed to killing of the microbes within the peritoneal cavity, but only elimination of polymer formation enhanced systemic dissemination. Host macrophage depletion or selective elimination of the fibrin(ogen) beta 2-integrin binding motif both compromised local bacterial killing and enhanced S. aureus systemic dissemination, suggesting fibrin polymer formation in and of itself was not sufficient to retain S. aureus within the peritoneal cavity. Collectively, these findings suggest that following peritoneal infection, the binding of S. aureus to stabilized fibrin matrices promotes a local, macrophage-mediated antimicrobial response essential for prevention of microbe dissemination and downstream host mortality.