fibrin and Toxoplasmosis

Toxoplasmosis is an important zoonotic disease that affects a wide range of warm-blooded host species. Neotropical primates (New World Primates; NWP) are highly susceptible, developing a lethal acute systemic disease. Toxoplasmosis in free-ranging NWP is poorly described, with only a few studies based on serosurveys. Herein we performed a retrospective study focusing on the epidemiology and pathology of toxoplasmosis among 1,001 free-ranging marmoset (Callithrix spp.) deaths from the Brazilian Atlantic Forest. This study included marmosets necropsied at the Instituto Municipal de Medicina Veterinária Jorge Vaitsman (IJV) from January 2017 to July 2019, which were found dead from all regions in the State of Rio de Janeiro. Histopathology, immunohistochemistry, and transmission electron microscopy were performed to better characterize toxoplasmosis in this free-ranging population. All samples were also tested for Yellow Fever Virus (YFV) RT-qPCR by the official diagnostic service. A total of 1,001 free-ranging marmosets were included in this study, with 16 (1.6%) cases of lethal Toxoplasma gondii infections identified both as individual cases and in outbreaks. Presence of infection was not associated with sex, age, geographical distribution, or year of death, and no co-infection with YFV was observed. The main pathological feature in these cases was random necrotizing hepatitis with detection of intralesional T. gondii zoites in all infected cases. Interstitial pneumonia rich in alveolar foamy macrophages and fibrin deposition, necrotizing myocarditis and necrotizing splenitis were also pathological features in affected marmosets. Therefore, toxoplasmosis was considered the cause of death in 1.6% of free-ranging marmosets in this retrospective series, including some cases associated with outbreaks. Necrotizing random hepatitis was a consistent pathological finding in affected cases and sampling of liver should be ensured from Callitrichid post mortem cases.

Topics: Animals; Brazil; Callithrix; Fibrin; Forests; Retrospective Studies; Toxoplasma; Toxoplasmosis; Yellow fever virus

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.

Topics: Acute Disease; Animals; Fibrin; Gene Expression Regulation; Hemorrhage; Humans; Interferon-gamma; Mice; Mice, Inbred C57BL; Toxoplasma; Toxoplasmosis; Tumor Necrosis Factor-alpha

Fibrinogen-like protein 2 (Fgl2, fibroleukin) is a leukocyte product that exhibits significant homology to secreted proteins of diverse function, including growth factors, lectins, and components of extracellular matrix. Prior studies found that Fgl2 is IFN gamma-inducible, possesses direct coagulant activity, and inhibits T cell proliferation and dendritic cell maturation in vitro. Here, we demonstrate that Fgl2 expression is up-regulated during type 1 immunity in vivo and establish that such up-regulation is IFN gamma-, signal transducer and activation of transcription protein 1-, and IFN response factor 1-dependent. To investigate functional roles for Fgl2 during type 1 immunity, we generated Fgl2-deficient mice. Those animals are born at predicted Mendelian frequencies, appear overtly healthy, and contain normal numbers and frequencies of lymphoid cells. Although Fgl2 is IFN gamma-inducible and putatively regulates T cell activation/proliferation, we demonstrate that Fgl2-deficient and control mice exhibit similar degrees of T cell expansion, immunopathology, and/or pathogen burdens during protozoan (Toxoplasma gondii), bacterial (Yersinia enterocolitica, Listeria monocytogenes, and Mycobacterium tuberculosis), and viral (murine gamma-herpesvirus-68 and Sendai) infections. Fgl2-deficient mice also reject allografts with similar kinetics as control mice. Moreover, despite prior reports that Fgl2 functions as a procoagulant enzyme, we demonstrate that Fgl2-deficient and control mice produce similar levels of fibrin, a product of the coagulation cascade, during T. gondii infection and allograft rejection. Together, our findings suggest that Fgl2, although highly conserved and IFN gamma-inducible, is not a critical mediator of either type 1 immunity or immune-associated coagulant activity.

Topics: Animals; Bacterial Infections; Blood Coagulation; Disease Models, Animal; DNA Primers; Fibrin; Heart Transplantation; Interferon-gamma; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger; T-Lymphocytes; Toxoplasmosis; Transplantation, Homologous; Virus Diseases

Fibrin, a product of the blood coagulation cascade, accompanies many type 1 immune responses, including delayed-type hypersensitivity, autoimmunity, and graft rejection. In those settings, fibrin is thought to exacerbate inflammation and disease. Here, we evaluate roles for coagulation during infection with Toxoplasma gondii, a pathogen whose control requires robust type 1 immunity. We establish that fibrin prevents infection-stimulated blood loss, thereby performing a protective function that is essential for survival. Remarkably, fibrin does not simply protect against vascular damage caused directly by the infectious agent, but rather, protects against hemorrhage evoked by interferon-gamma, a critical mediator of type 1 immunity. This finding, to our knowledge, is the first to document a beneficial role for coagulation during type 1 immunity, and suggests that fibrin deposition protects host tissue from collateral damage caused by the immune system as it combats infection.

Topics: Animals; Blood Coagulation; Fibrin; Immunity; Interferon-gamma; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Survival Rate; Toxoplasma; Toxoplasmosis