Submitted July 22, 2008
Accepted November 25, 2008
Reduced thrombin generation increases host susceptibility to group A streptococcal infection
Hongmin Sun, Xixi Wang, Jay L. Degen, and David Ginsburg*
Department of Internal Medicine, University of Missouri-Columbia, Columbia, MO, United States
Life Science Institute, University of Michigan, Ann Arbor, MI, United States
Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
Howard Hughes Medical Institute, Ann Arbor, MI, United States
* Corresponding author; email: ginsburg{at}umich.edu.
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 (SK), a specific activator of human plasminogen (PLG). The critical contribution of the SK-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 FV in either the plasma or platelet compartment. Reduction of FV in either pool resulted in markedly increased mortality following 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. Though 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.
