Severe sepsis and septic shock secondary to Gram-positive bacterial pathogen infection is increasingly recognized in a recent series of patients with sepsis from the USA and other developed countries. While the molecular pathogenesis of Gram-negative bacterial sepsis and endotoxin-mediated cellular events are increasingly well understood, the molecular nature of microbial pathogenesis secondary to Gram-positive bacterial pathogens remains less well understood. Superantigen-mediated immunopathogenic mechanisms are well described but the pathogenesis of non-superantigen-producing Gram-positive pathogens is less well understood. A major bacterial pathogen in recent studies of septic shock has been the enterococcal species. These Gram-positive bacterial organisms are intrinsically resistant to numerous antimicrobial agents and have a propensity for rapid development of resistance to broad-spectrum antibacterial agents including vancomycin, aminoglycosides, and extended spectrum beta-lactam antimicrobial agents. It has been previously observed that enterococcal species, in contrast to other Gram-positive bacterial pathogens, are more likely to cause lethality in D-galactosamine-treated mice. D-galactosamine treatment potentiates TNF-mediated lethality in this rodent model. These data indicate that TNF is important in the lethality associated with enterococcal sepsis. Further support for this hypothesis is found in corticosteroid-treated animals. Corticosteroids attenuate TNF-induced lethality in gram-negative bacterial sepsis models. This steroid-induced attenuation is observed with enterococci but not other Gram-positive bacterial pathogens tested thus far. It was observed that Enterococcus faecalis was a poor inducer of TNF in an in vitro system that examines TNF production in peritoneal macrophages. The investigators hypothesize that Enterococcal species must synergize with bacterial LPS in Gram-negative bacteria in order to induce a lethal systemic inflammatory response. The proposal will investigate the general nature of enterococcal sepsis through a series of experiments. First, the investigators plan to test a wider array of Gram-positive pathogens including other species of enterococci to determine the potential unique position of Enterococcus species in the generation of a lethal systemic bacterial infection. Next the investigators will use an anti-TNF monoclonal antibody as well as a TNF knockout mouse in addition to an LPS hyporesponsive mouse model and a lipopolyamine anti-endotoxin agent in combination with enterococcal bacterial challenge to examine the relative roles of TNF and endotoxin in enterococcal sepsis.
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