In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 1 ( 2022-1-18), p. e1010227-
Kurzfassung:
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 Fibγ Δ5 mice, which express a mutant form lacking the final 5 amino acids of the fibrinogen γ chain (termed fibrinogenγ Δ5 ), 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, Fibγ Δ5 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.
Materialart:
Online-Ressource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010227
DOI:
10.1371/journal.ppat.1010227.g001
DOI:
10.1371/journal.ppat.1010227.g002
DOI:
10.1371/journal.ppat.1010227.g003
DOI:
10.1371/journal.ppat.1010227.g004
DOI:
10.1371/journal.ppat.1010227.g005
DOI:
10.1371/journal.ppat.1010227.g006
DOI:
10.1371/journal.ppat.1010227.g007
DOI:
10.1371/journal.ppat.1010227.s001
DOI:
10.1371/journal.ppat.1010227.s002
DOI:
10.1371/journal.ppat.1010227.s003
DOI:
10.1371/journal.ppat.1010227.s004
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2022
ZDB Id:
2205412-1
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