title: Genetic elimination of the binding motif on fibrinogen for the S. aureus virulence factor ClfA improves host survival in septicemia.
abstract: Fibrinogen can support host antimicrobial containment/clearance mechanisms, yet selected pathogens appear to benefit from host procoagulants to drive bacterial virulence. Here, we explored the hypothesis that host fibrin(ogen), on balance, supports Staphylococcus aureus infection in the context of septicemia. Survival studies following intravenous infection in control and fibrinogen-deficient mice established the overall utility of host fibrin(ogen) to S. aureus virulence. Complementary studies in mice expressing mutant forms of fibrinogen-retaining clotting function, but lacking either the bacterial ClfA (Fibγ(Δ5)) binding motif or the host leukocyte integrin receptor αMβ2 (Fibγ(390-396A)) binding motif, revealed the preeminent importance of the bacterial ClfA-fibrin(ogen) interaction in determining host survival. Studies of mice lacking platelets or the platelet integrin receptor subunit αIIb established that the survival benefits observed in Fibγ(Δ5) mice were largely independent of platelet αIIbβ3-mediated engagement of fibrinogen. Fibγ(Δ5) mice exhibited reduced bacterial burdens in the hearts and kidneys, a blunted host proinflammatory cytokine response, diminished microscopic tissue damage, and significantly diminished plasma markers of cardiac and other organ damage. These findings indicate that host fibrin(ogen) and bacterial ClfA are dual determinants of virulence and that therapeutic interventions at the level of fibrinogen could be advantageous in S. aureus septicemia.
authors.affiliation: Division of Experimental Hematology and Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.forename: XinLi
authors.initials: X
authors.lastname: Du
authors.forename: Joni M
authors.initials: JM
authors.lastname: Prasad
authors.forename: Harini
authors.initials: H
authors.lastname: Raghu
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Palumbo
authors.forename: Emanuel
authors.initials: E
authors.lastname: Smeds
authors.forename: Magnus
authors.initials: M
authors.lastname: Höök
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
mesh_terms: D000347:Afibrinogenemia / Q000209:etiology; D000818:Animals; D001422:Bacterial Adhesion / Q000502:physiology; D001665:Binding Sites; D003030:Coagulase / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D005340:Fibrinogen / Q000502:physiology*; D005434:Flow Cytometry; D016177:Macrophage-1 Antigen / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018805:Sepsis / Q000209:etiology / Q000401:mortality* / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000150:complications / Q000276:immunology / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000378:metabolism / Q000472:pathogenicity*; D015996:Survival Rate; D014774:Virulence / Q000502:physiology*
chemical_list: C515944:ClfA protein, Staphylococcus aureus; D003030:Coagulase; D016207:Cytokines; D016177:Macrophage-1 Antigen; D005340:Fibrinogen