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 FibγΔ5 mice, which express a mutant form lacking the final 5
amino acids of the
fibrinogen γ chain (termed fibrinogenγΔ5), 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, FibγΔ5 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) β2-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.