title: Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense.
abstract: Fibrin(ogen) is central to hemostasis and thrombosis and also contributes to multiple physiologic and pathologic processes beyond coagulation. However, the precise contribution of soluble fibrinogen vs insoluble fibrin matrices to vascular integrity, tissue repair, inflammation, and disease has been undefined and unapproachable. To establish the means to distinguish fibrinogen- and fibrin-dependent processes in vivo, Fib(AEK) mice were generated that carry normal levels of circulating fibrinogen but lack the capacity for fibrin polymer formation due to a germ-line mutation in the Aα chain thrombin cleavage site. Homozygous Fib(AEK) mice developed to term and exhibited postnatal survival superior to that of fibrinogen-deficient mice. Unlike fibrinogen-deficient mice, platelet-rich plasma from Fib(AEK) mice supported normal platelet aggregation in vitro, highlighting that fibrinogen(AEK) retains the functional capacity to support interactions with platelets. Thrombin failed to release fibrinopeptide-A from fibrinogen(AEK) and failed to induce polymer formation with Fib(AEK) plasma or purified fibrinogen(AEK) in 37°C mixtures regardless of incubation time. Fib(AEK) mice displayed both an absence of fibrin polymer formation following liver injury, as assessed by electron microscopy, and a failure to generate stable occlusive thrombi following FeCl3 injury of carotid arteries. Fib(AEK) mice exhibited a profound impediment in Staphylococcus aureus clearance following intraperitoneal infection similar to fibrinogen-deficient mice, yet Fib(AEK) mice displayed a significant infection dose-dependent survival advantage over fibrinogen-deficient mice following peritonitis challenge. Collectively, these findings establish for the first time that fibrin polymer is the molecular form critical for antimicrobial mechanisms while simultaneously highlighting biologically meaningful contributions and functions of the soluble molecule.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
authors.forename: Joni M
authors.initials: JM
authors.lastname: Prasad
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Gorkun
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
authors.forename: Harini
authors.initials: H
authors.lastname: Raghu
authors.affiliation: Division of Rheumatology.
authors.forename: Sherry
authors.initials: S
authors.lastname: Thornton
authors.affiliation: Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
authors.forename: Eric S
authors.initials: ES
authors.lastname: Mullins
authors.affiliation: Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Palumbo
authors.affiliation: Center for Infectious and Inflammatory Diseases, Institute for Biosciences and Technology, Texas A&M Health Science Center, Houston, TX; and.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Ko
authors.affiliation: Center for Infectious and Inflammatory Diseases, Institute for Biosciences and Technology, Texas A&M Health Science Center, Houston, TX; and.
authors.forename: Magnus
authors.initials: M
authors.lastname: Höök
authors.affiliation: Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA.
authors.forename: Tovo
authors.initials: T
authors.lastname: David
authors.affiliation: Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Coughlin
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
mesh_terms: D000818:Animals; D001780:Blood Coagulation Tests; D002478:Cells, Cultured; D005337:Fibrin / Q000378:metabolism*; D005340:Fibrinogen / Q000502:physiology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006490:Hemostatics; D054884:Host-Pathogen Interactions; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D010538:Peritonitis / Q000209:etiology* / Q000473:pathology; D010974:Platelet Aggregation; D013203:Staphylococcal Infections / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000276:immunology*
chemical_list: D006490:Hemostatics; D005337:Fibrin; D005340:Fibrinogen