54 research outputs found
Protective Roles for Fibrin, Tissue Factor, Plasminogen Activator Inhibitor-1, and Thrombin Activatable Fibrinolysis Inhibitor, but Not Factor XI, during Defense against the Gram-Negative Bacterium Yersinia enterocolitica
Septic infections dysregulate hemostatic pathways, prompting coagulopathy. Nevertheless, anticoagulant therapies typically fail to protect humans from septic pathology. The data reported here may help to explain this discrepancy by demonstrating critical protective roles for coagulation leading to fibrin deposition during host defense against the gram-negative bacterium Yersinia enterocolitica. After intraperitoneal inoculation with Y. enterocolitica, fibrinogen-deficient mice display impaired cytokine and chemokine production in the peritoneal cavity and suppressed neutrophil recruitment. Moreover, both gene-targeted fibrinogen-deficient mice and wild type mice treated with the anticoagulant coumadin display increased hepatic bacterial burden and mortality following either intraperitoneal or intravenous inoculation with Y. enterocolitica. Mice with low tissue factor (TF) activity succumb to yersiniosis with a phenotype similar to fibrin(ogen)-deficient mice, whereas factor XI (FXI)-deficient mice show wild type levels of resistance. Mice deficient in plasminogen activator inhibitor-1 (PAI-1) or thrombin activatable fibrinolysis inhibitor (TAFI) display modest phenotypes, but mice deficient in both PAI-1 and TAFI succumb to yersiniosis with a phenotype resembling fibrin(ogen)-deficient mice. These findings demonstrate critical protective roles for the TF-dependent extrinsic coagulation pathway during host defense against bacteria and caution that therapeutics targeting major thrombin-generating or anti-fibrinolytic pathways may disrupt fibrin-mediated host defense during gram-negative sepsis
Fibrin Facilitates Both Innate and T Cell-Mediated Defense against Yersinia pestis
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 non-diffusible 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 antibody-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 in order to withstand Y. pestis encounters and effectively clear bacteria
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MEGAPOLI: concept of multi-scale modelling of megacity impact on air quality and climate
The EU FP7 Project MEGAPOLI: "Megacities: Emissions, urban, regional and Global Atmospheric POLlution and climate effects, and Integrated tools for assessment and mitigation" (http://megapoli.info) brings together leading European research groups, state-of-the-art scientific tools and key players from non-European countries to investigate the interactions among megacities, air quality and climate. MEGAPOLI bridges the spatial and temporal scales that connect local emissions, air quality and weather with global atmospheric chemistry and climate. The suggested concept of multi-scale integrated modelling of megacity impact on air quality and climate and vice versa is discussed in the paper. It requires considering different spatial and temporal dimensions: time scales from seconds and hours (to understand the interaction mechanisms) up to years and decades (to consider the climate effects); spatial resolutions: with model down- and up-scaling from street- to global-scale; and two-way interactions between meteorological and chemical processes
D27-pLpxL, an Avirulent Strain of Yersinia pestis, Primes T Cells That Protect against Pneumonic Plagueâ–¿
Vaccinating with live, conditionally attenuated, pigmentation (Pgm)-deficient Yersinia pestis primes T cells that protect mice against pneumonic plague. However, Pgm-deficient strains are not considered safe for human use because they retain substantial virulence in animal models. Y. pestis strains engineered to express Escherichia coli LpxL are avirulent owing to constitutive production of lipopolysaccharide with increased Toll-like receptor 4-activating ability. We generated an LpxL-expressing Pgm-deficient strain (D27-pLpxL) and demonstrate here that this avirulent strain retains the capacity to prime protective T cells. Compared with unvaccinated controls, mice immunized intranasally with live D27-pLpxL exhibit a decreased bacterial burden and increased survival when challenged intranasally with virulent Y. pestis. T cells provide a substantial degree of this protection, as vaccine efficacy is maintained in B-cell-deficient μMT mice unless those animals are depleted of CD4 and CD8 T cells at the time of challenge. Upon challenge with Y. pestis, pulmonary T-cell numbers decline in naive mice, whereas immunized mice show increased numbers of CD44high CD43high effector T cells and T cells primed to produce tumor necrosis factor alpha and gamma interferon; neutralizing these cytokines at the time of challenge abrogates protection. Immunization does not prevent dissemination of Y. pestis from the lung but limits bacterial growth and pathology in visceral tissue, apparently by facilitating formation of granuloma-like structures. This study describes a new model for studying T-cell-mediated protection against pneumonic plague and demonstrates the capacity for live, highly attenuated, Y. pestis vaccine strains to prime protective memory T-cell responses safely
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