ROLE OF LOS AND ITS RECEPTORS IN GONOCOCCAL PATHEGENEIS

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Description (Adapted from the applicant's abstract): Neisseria gonorrhoeae is a major cause of sexually transmitted diseases. While this organism primarily infects the lower genital tract, it can ascend to the upper female genital tract, and certain strains are capable of dissemination. Early events in the establishment of infection involve interactions between N. gonorrhoeae and cells present in the human genital tract. Here, surface antigens on the gonococcus trigger the local and systemic humoral immune response that results in the release of cytokines, prostaglandins, and other inflammatory mediators. Previous efforts have focused on defining immunologic responses to protein antigens on the surface of N. gonorrhoeae. In contrast, little attention has been paid to the pro-inflammatory effects of the endotoxin lipopolysaccharide, LPS) that coats the surface of all Gram-negative bacteria, including the gonococcus. With Neisseria meningitidis, as well as most enteric Gram-negative pathogens, it is clear that the acute cytokine response associated with the sepsis syndrome is due, in a large part, to the interaction of LPS with its receptors. For N. gonorrhoeae, however, the role of its endotoxin (also known as lipooligosaccharide or LOS) their responsiveness to various strains of gonococci and their LOSs. These in the activation of epithelial cells encountered during mucosal infection of the genital tract are unproven, although its pro-inflammatory activity in vitro has been documented. The goal of this proposal is to characterize the role of gonococcal LOS in the interaction between N. gonorrhoeae and the epithelial cells found in the female genital tract. First, the PI will characterize three novel epithelial cell lines derived from the female genital tract in terms of cell lines may represent a new in vitro model for examining the pathogenesis of gonococcal infections. Second, the PI will make two mutants in the lipid A component of gonococcal LOS. Lipid A has been shown to be responsible for the pro-inflammatory effects of LPS, and loss or modification of lipid A would be expected to impact o the pathogenicity of a Gram-negative bacterium. Finally, the PI will examine the role of epithelial cell receptors for endotoxin in gonococcal invasion and activation, with an emphasis on Toll, a family of receptors recently identified as components of the LPS signaling pathway.