fibrin and Plague

Fibrin has been demonstrated to function protectively against pathogens in our previous studies, but we observed that a very high level of fibrin played a negative role during infection. We performed this research to address the complication.. After infection, mice were monitored daily and harvested on day 4. The fibrin levels within the tissue samples were quantified by Western-blot. The in situ assay was used to detect plasminogen activators, protein C-ase and prothrombinase activation. PT-PCR was used to test coagulation factors expression.. Mice treated with Coumadin showed that the protection correlates with fibrin levels. By interacting with Toll-like receptor 4, the hexa-acylated lipopolysaccharide, although not the tetra-acylated lipopolysaccharide, activates coagulation and regulates plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor and thrombomodulin expression through myeloid differentiation factor 88, leading to plasminogen activators, protein C-ase and prothrombinase activation and fibrin formation. Because of the regulation, fibrin formation was controlled to deposit appropriate levels and confer protection.. We demonstrated that the appropriate level of fibrin formation was deployed by hexa-acylated LPS-lipid A through myeloid differentiation factor 88 to confer protection.

Topics: Animals; Blood Coagulation; Fibrin; Lipid A; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Plague; Plasminogen Activator Inhibitor 1; Plasminogen Activators; Protein C; Thrombomodulin; Toll-Like Receptor 4

The Gram-negative bacterium Yersinia pestis causes plague, a rapidly progressing and often fatal disease. The formation of fibrin at sites of Y. pestis infection supports innate host defense against plague, perhaps by providing a nondiffusible spatial cue that promotes the accumulation of inflammatory cells expressing fibrin-binding integrins. This report demonstrates that fibrin is an essential component of T cell-mediated defense against plague but can be dispensable for Ab-mediated defense. Genetic or pharmacologic depletion of fibrin abrogated innate and T cell-mediated defense in mice challenged intranasally with Y. pestis. The fibrin-deficient mice displayed reduced survival, increased bacterial burden, and exacerbated hemorrhagic pathology. They also showed fewer neutrophils within infected lung tissue and reduced neutrophil viability at sites of liver infection. Depletion of neutrophils from wild-type mice weakened T cell-mediated defense against plague. The data suggest that T cells combat plague in conjunction with neutrophils, which require help from fibrin to withstand Y. pestis encounters and effectively clear bacteria.

Topics: Animals; Bacterial Proteins; Fibrin; Fibrinogen; Immunity, Innate; Mice; Mice, Inbred C57BL; Mice, Knockout; Plague; Plasminogen Activators; T-Lymphocyte Subsets; Yersinia pestis

Topics: Animals; Bacterial Proteins; Fibrin; Humans; Plague; Plasminogen Activators; Yersinia pestis

Plasminogen-deficient mice hold great promise as tools for analyzing the contribution of plasminogen activators produced by infectious agents to pathogenesis. However, the pathology caused by congenital plasminogen deficiency complicates the interpretation of infection experiments conducted with these animals. This pathology, the most prominent features of which are poor weight gain, wasting after about 60 days of age, and shortened lifespan, results from the inability of the mice to clear small fibrin thrombi. This article describes strategies for distinguishing the contribution of this pathology from the direct effects of depriving infectious agents of plasminogen. These strategies depend on the use of mouse genotypes in which the correlation of plasminogen deficiency with fibrin-dependent pathology is broken. Mice with plasminogen activator deficiencies are unable to generate plasmin and develop pathologies identical to those seen in plasminogen-deficient mice. However, unlike plasminogen-deficient mice, they do make plasminogen available to the infectious agent. Fibrinogen-deficient mice also deficient for plasminogen do not develop the pathology typical of plasminogen deficiency. These mice allow examination of plasminogen deficiency in the absence of fibrin-dependent pathology. Use of fibrinogen-deficient mice is complicated by the possibility that fibrin may be the key substrate of plasmin generated by the infectious agent.

Topics: Animals; Fibrin; Mice; Mice, Knockout; Plague; Plasminogen; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Yersinia pestis

Plague is a deadly disease of obvious concern to individuals, communities, and public health officials. The rapid recognition of plague victims is of paramount importance in saving the lives of the victims and in the protection of contacts. Three autopsied plague cases have been presented and the pathological features have been discussed.

Topics: Adolescent; Autopsy; Child, Preschool; Female; Fibrin; Humans; Male; New Mexico; Plague; Thrombosis; Yersinia pestis