fibrin and Orthomyxoviridae-Infections

Epidemiological studies relate influenza infection with vascular diseases like myocardial infarction. The hypothesis that influenza infection has procoagulant effects on humans has been investigated by experimental animal models. However, these studies often made use of animal models only susceptible to adapted influenza viruses (mouse adapted influenza strains) or remained inconclusive. Therefore, we decided to study the influence of infection with human influenza virus isolates on coagulation in the well-established ferret influenza model.. After infection with either a seasonal-, pandemic- or highly pathogenic avian influenza (HPAI-H5N1) virus strain infected animals showed alterations in hemostasis compared to the control animals. Specifically on day 4 post infection, a four second rise in both PT and aPTT was observed. D-dimer concentrations increased in all 3 influenza groups with the highest concentrations in the pandemic influenza group. Von Willebrand factor activity levels increased early in infection suggesting endothelial cell activation. Mean thrombin-antithrombin complex levels increased in both pandemic and HPAI-H5N1 virus infected ferrets. At tissue level, fibrin staining showed intracapillary fibrin deposition especially in HPAI-H5N1 virus infected ferrets.. This study showed hemostatic alterations both at the circulatory and at the tissue level upon infection with different influenza viruses in an animal model closely mimicking human influenza virus infection. Alterations largely correlated with the severity of the respective influenza virus infections.

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Disease Models, Animal; Ferrets; Fibrin; Fibrin Fibrinogen Degradation Products; Histocytochemistry; Lung; Male; Orthomyxoviridae Infections; Partial Thromboplastin Time; Thrombin Time; von Willebrand Factor

Detrimental inflammation of the lungs is a hallmark of severe influenza virus infections. Endothelial cells are the source of cytokine amplification, although mechanisms underlying this process are unknown. Here, using combined pharmacological and gene-deletion approaches, we show that plasminogen controls lung inflammation and pathogenesis of infections with influenza A/PR/8/34, highly pathogenic H5N1 and 2009 pandemic H1N1 viruses. Reduction of virus replication was not responsible for the observed effect. However, pharmacological depletion of fibrinogen, the main target of plasminogen reversed disease resistance of plasminogen-deficient mice or mice treated with an inhibitor of plasminogen-mediated fibrinolysis. Therefore, plasminogen contributes to the deleterious inflammation of the lungs and local fibrin clot formation may be implicated in host defense against influenza virus infections. Our studies suggest that the hemostatic system might be explored for novel treatments against influenza.

Topics: Animals; Antiviral Agents; Female; Fibrin; Fibrin Clot Lysis Time; Fibrinogen; Fibrinolysis; Fibrinolytic Agents; Host-Pathogen Interactions; Inflammation; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Orthomyxoviridae Infections; Plasminogen; Pneumonia, Viral; Virus Replication

Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3-induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected Par1(-/-) mice expressed reduced levels of IFN-β and CXCL10 during the early phase of infection compared with Par1(+/+) mice that resulted in higher viral loads and cardiac injury at day 8 after infection. Inhibition of either tissue factor or thrombin in WT mice also significantly increased CVB3 levels in the heart and cardiac injury compared with controls. BM transplantation experiments demonstrated that PAR-1 in nonhematopoietic cells protected mice from CVB3 infection. Transgenic mice overexpressing PAR-1 in cardiomyocytes had reduced CVB3-induced myocarditis. We found that cooperative signaling between PAR-1 and TLR3 in mouse cardiac fibroblasts enhanced activation of p38 and induction of IFN-β and CXCL10 expression. Par1(-/-) mice also had decreased CXCL10 expression and increased viral levels in the lung after influenza A infection compared with Par1(+/+) mice. Our results indicate that the tissue factor/thrombin/PAR-1 pathway enhances IFN-β expression and contributes to the innate immune response during single-stranded RNA viral infection.

Topics: Animals; Chemokine CXCL10; Coxsackievirus Infections; Enterovirus; Fibrin; HEK293 Cells; HeLa Cells; Humans; Immunity, Innate; Influenza A virus; Interferon-beta; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocarditis; Myocardium; Orthomyxoviridae Infections; Receptor, PAR-1; STAT1 Transcription Factor; Thrombin; Thromboplastin; Toll-Like Receptor 3; Troponin I

Topics: Animals; Antigens; Blood Vessels; Bronchi; Fibrin; Fluorescent Antibody Technique; gamma-Globulins; Lung; Mice; Orthomyxoviridae; Orthomyxoviridae Infections; Pneumonia; Pulmonary Artery; Pulmonary Veins; Time Factors

Topics: Animals; Antigen-Antibody Reactions; Blood Vessels; Fibrin; Fluorescent Antibody Technique; gamma-Globulins; Liver; Mice; Orthomyxoviridae; Orthomyxoviridae Infections

Topics: Animals; Antigen-Antibody Reactions; Antigens; Fibrin; Fluorescent Antibody Technique; gamma-Globulins; Lymph Nodes; Mice; Orthomyxoviridae; Orthomyxoviridae Infections; Spleen