The role of inflammasome signaling in the pathogenesis of gonococcal disease

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Neisseria gonorrhoeae (gonococcus or GC) is one of the most common sexually transmitted pathogens in the world. N. gonorrhoeae depends on numerous, highly adapted host-pathogen interactions to persist in the human urogenital tract. Localized gonococcal infection is often characterized by paradoxical immunologic findings that include localized inflammation but limited, and non-protective, adaptive immune responses. At the same time, disseminated gonococcal diseases are often associated with mucosal colonization by N. gonorrhoeae that fails to stimulate the host inflammatory response that is a hallmark of localized infections. The mechanisms by which N. gonorrhoeae induces this paradoxical host response are thought to involve both antigenic variation and active manipulation of immune system signaling by the infecting bacteria Gonococcal infection, in human men is associated with production of inflammatory cytokines, including IL-. Ibeta. We have recently found that N. gonorrhoeae induces IL-1 beta production by activation of a host pathogen recognition signaling system known as the inflammasome. Activation of the inflammasome also induces a recently identified program of cell death known as pyronecrosis. Unlike apoptosis, pyronecrosis is a proinflammatory process resulting in the release of intracellular contents which act as inflammatory mediators. The gonococcus activates this pathway more potently than commensal Neisseria species and does so through the the release of factors into the environment, suggesting that activation of the pathway may be related to virulence of N. gonorrhoeae. There are multiple mechanisms by which N. gonorrhoeae may preferentially activate the NLRP3 signaling pathway. In collaboration with several SE STI CRC investigators, we propose a series of studies to investigate the host and pathogen factors involved in activation of this signaling pathway and its involvement in innate and adaptive immune responses to N. gonorrhoeae