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ABSTRACT: Bacterial plasminogen activators are commonplace among microbial pathogens, implying a central role of host plasmin in supporting bacterial virulence. Group A streptococci (GAS) secrete streptokinase, a specific activator of human plasminogen (PLG). The critical contribution of the streptokinase-PLG interaction to GAS pathogenicity was recently demonstrated using mice expressing human PLG. To examine the importance of thrombin generation in antimicrobial host defense, we challenged mice with deficiency of factor V (FV) in either the plasma or platelet compartment. Reduction of FV in either pool resulted in markedly increased mortality after GAS infection, with comparison to heterozygous F5-deficient mice suggesting a previously unappreciated role for the platelet FV pool in host defense. Mice with complete deficiency of fibrinogen also demonstrated markedly increased mortality to GAS infection relative to controls. Although FV Leiden may be protective in the setting of severe sepsis in humans, no significant survival advantage was observed in GAS-infected mice carrying the FV Leiden mutation. Taken together, our data support the hypothesis that local thrombosis/fibrin deposition limits the survival and dissemination of at least a subset of microbial pathogens and suggest that common variation in hemostatic factors among humans could affect host susceptibility to a variety of infectious diseases.
Blood 01/2009; 113(6):1358-64. · 9.90 Impact Factor
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ABSTRACT: Group A streptococci, a common human pathogen, secrete streptokinase, which activates the host's blood clot-dissolving protein, plasminogen. Streptokinase is highly specific for human plasminogen, exhibiting little or no activity against other mammalian species, including mouse. Here, a transgene expressing human plasminogen markedly increased mortality in mice infected with streptococci, and this susceptibility was dependent on bacterial streptokinase expression. Thus, streptokinase is a key pathogenicity factor and the primary determinant of host species specificity for group A streptococcal infection. In addition, local fibrin clot formation may be implicated in host defense against microbial pathogens.
Science 09/2004; 305(5688):1283-6. · 31.20 Impact Factor
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ABSTRACT: Coagulation factor V (FV) is a central regulator of the coagulation cascade. Circulating FV is found in plasma and within platelet alpha granules. The specific functions of these distinct FV pools are uncertain. We now report the generation of transgenic mice with FV gene expression restricted to either the liver or megakaryocyte/platelet lineage using bacterial artificial chromosome (BAC) constructs. Six of 6 independent albumin BAC transgenes rescue the neonatal lethal hemorrhage of FV deficiency. Rescued mice all exhibit liver-specific Fv expression at levels ranging from 6% to 46% of the endogenous Fv gene, with no detectable FV activity within the platelet pool. One of the 3 Pf4 BAC transgenes available for analysis also rescues the lethal FV null phenotype, with FV activity restricted to only the platelet pool (approximately 3% of the wild-type FV level). FV-null mice rescued by either the albumin or Pf4 BAC exhibit nearly normal tail bleeding times. These results demonstrate that Fv expression in either the platelet or plasma FV pool is sufficient for basal hemostasis. In addition, these findings indicate that the murine platelet and plasma FV pools are biosynthetically distinct, in contrast to a previous report demonstrating a plasma origin for platelet FV in humans.
Blood 11/2003; 102(8):2856-61. · 9.90 Impact Factor
