The human pathogen Neisseria gonorrhoeae produces an array of diseases ranging from urethritis and cervicitis, to pelvic inflammatory disease. Early events in the establishment of infection involve interactions between N. gonorrhoeae and mucosal epithelial cells, which leads to colonization of the mucosal surface, the local release of inflammatory mediators, and the recruitment of professional immune cells. The innate immune system is the first line of defense against invading microorganisms. Toll-like receptors (TLRs) are a part of this innate immune defense, recognizing conserved microbial patterns and initiating signal transduction pathways that direct the inflammatory response. These germ-line encoded proteins are expressed to varying degrees in both professional and non-professional immune cells. While phagocytic cells express an array of TLRs, mucosal epithelial cells express a more selective repertoire that limits their ability to respond to some microbial ligands. Thus, it is the coordination of epithelial and phagocytic cell responses to this pathogen that results in the protective immune response that leads to bacterial clearance and resolution of infection. Our preliminary data demonstrates a role for interactions between bacterial lipopolysaccharide (LPS) and host TLR4 in the early inflammatory response of the lower female reproductive tract (FRT). Furthermore, we have shown that inbred mouse strains differ in their ability to support colonization with N. gonorrhoeae and induce a neutrophil influx. We hypothesize that TLR4 expressed on professional phagocytic cells present or recruited to the FRT plays a key role in initiating the early inflammatory response that is responsible for bacterial clearance during mucosal infections with gonorrhea. Furthermore, we believe additional host factors render the subject susceptible to colonization with gonorrhea, and that some hosts may be more naturally resistant than others to infection. The basis of this natural resistance is yet undefined, but is likely to be multigenic. In order to test these hypotheses we propose the following three Specific Aims: (1) To determine if naturally occurring mutations in gonococcal LPS might account for differences in the host inflammatory response to infection; (2) To determine if polymorphisms in the TLR4 adaptor Mai might account for differences in the host inflammatory response to infection; and (3) To detemnine the genetic basis for resistance to infection in inbred mouse strains.

Gonorrhea is a common sexually transmitted infection in the U.S. Women usually have few or no symptoms associated with infection, which often leads to delays in treatment and the development of complications such as pelvic inflammatory disease and infertility. We believe that a better understanding of the innate immune response to this pathogen will lead to treatments that can lessen the complications associated with infection and support the development of protective vaccine strategies