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

Abstract

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.

Helicobacter pylori eradication reduces risk for recurrence of gastric hyperplastic polyp after endoscopic resection

“…Additionally, it is possible to hypothesize that anticoagulants may influence inflammation and immune responses against H. pylori infection by inhibiting the coagulation cascade. Fibrin, an end product of the coagulation cascade, is known to play a protective role during infection by limiting bacterial dissemination and activating the antimicrobial properties of monocytes and macrophages [27,28]. A previous study showed an increased level of fibrin in the gastric mucosa of H. pyloripositive patients [29].…”

Whole-genome analysis showed the promotion of genetic diversity and coevolution in Staphylococcus aureus lytic bacteriophages and their hosts mediated by prophages via worldwide recombination events

“…S. aureus strains that secrete exotoxins and exoenzymes can disrupt endothelial and epithelial barriers via cell lysis and junction protein cleavage (Tam and Torres, 2019). Adhesins allow S. aureus to attach to host cells and the extracellular matrix during the early colonization phase (Negron et al, 2022). Nutritional/metabolic factors are critical for the fitness of S. aureus and its adaptation to nutritionally diverse environments (Balasubramanian et al, 2017).…”

Antibodies to Coagulase ofStaphylococcus aureuscrossreact to Efb and reveal different binding of shared Fibrinogen binding repeats

“…Among these interactions, Fg seems to play a dominant role (8) Also the role of Fg is at the crossroad between its well described role in haemostasis and its importance in mediating immune response (14,48). Much preclinical evidence also showed that mutated versions of Fg cannot efficiently clear infection mediated by S. aureus thus compromising immune response towards the pathogen (19)(20)(21)49). Furthermore, preclinical studies together with vaccine candidates have shown that ClfA-mediated Fg interaction is a viable alternative for possible therapeutic strategies (50)(51)(52).…”

“…Multiple recent evidence has demonstrated that the interaction with Fg may drive different host responses based on the tissutal context (8). In peritonitis mouse infection models, binding of Fg is fundamental to elicit an antibacterial response and contain infection (18)(19)(20)(21). However, the picture is completely reversed in bloodstream infections, where Fg instead promotes spreading of S. aureus (22).…”