title: Tumor necrosis factor alpha and gamma interferon, but not hemorrhage or pathogen burden, dictate levels of protective fibrin deposition during infection.
abstract: While coagulation often causes pathology during infectious disease, we recently demonstrated that fibrin, a product of the coagulation pathway, performs a critical protective function during acute toxoplasmosis (L. L. Johnson, K. N. Berggren, F. M. Szaba, W. Chen, and S. T. Smiley, J. Exp. Med. 197:801-806, 2003). Here, we investigate the mechanisms regulating the formation of this protective fibrin. Through comparisons of Toxoplasma-infected wild-type and cytokine-deficient mice we dissociate, for the first time, the relative fibrin-regulating capacities of pathogen products, host cytokines, and infection-stimulated hemorrhage. Remarkably, neither the pathogen burden nor hemorrhage is a primary regulator of fibrin levels. Rather, two type 1 cytokines exert dominant and counterregulatory roles: tumor necrosis factor alpha (TNF-alpha), acting via the type 1 TNF-alpha receptor, promotes fibrin deposition, while gamma interferon (IFN-gamma), acting via STAT1 and IFN-gamma receptors expressed on radioresistant cells, suppresses fibrin deposition. These findings have important clinical implications, as they establish that cytokines known to regulate pathological coagulation also dictate levels of protective fibrin deposition. We present a novel model depicting mechanisms by which the immune system can destroy infected tissue while independently restraining hemorrhage and promoting tissue repair through the deliberate deposition of protective fibrin.
authors.affiliation: Trudeau Institute, 154 Algonquin Ave., Saranac Lake, NY 12983, USA.
authors.forename: Isis K
authors.initials: IK
authors.lastname: Mullarky
authors.forename: Frank M
authors.initials: FM
authors.lastname: Szaba
authors.forename: Kiera N
authors.initials: KN
authors.lastname: Berggren
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Kummer
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Wilhelm
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Parent
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Johnson
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smiley
mesh_terms: D000208:Acute Disease; D000818:Animals; D005337:Fibrin / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D006470:Hemorrhage / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D014122:Toxoplasma / Q000302:isolation & purification / Q000472:pathogenicity*; D014123:Toxoplasmosis / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005337:Fibrin