Proinflammatory cytokines are expressed in vivo during infection with the sexually transmitted disease pathogen Neisseria gonorrhoeae and contribute to disease pathology. The activation of proinflammatory cytokines is directed by pattern recognition receptors (PRRs). PRRs can be classified as transmembrane molecules such at the Toll-like receptors (TLRs), or cytosolic molecules including Nod- like receptors (NLRs). TLR2 and TLR4 function as receptors for Neisseria ligands. However, nothing is known about cytosolic molecules that respond to intracellular N. gonorrhoeae. We recently demonstrated that blocking signaling through TLRs using antagonistic antibodies only partially reduced the production of proinflammatory cytokines following N. gonorrhoeae infection of epithelial cells suggesting that intracellular NLRs may be employed for N. gonorrhoeae induced proinflammatory cytokines. We also demonstrated that infection of epithelial cells with N. gonorrhoeae induced the expression of NLRs including Nodi and a protein recently implicated in intracellular immune recognition, inhibitor of apoptosis protein (clAP-2), as well as the receptor interacting serine-threonine kinase 2 (R1P2), a key mediator of innate immune signaling. Furthermore, we established that N. gonorrhoeae stimulates proinflammatory cytokine responses through Nod1 and Nod 2 in an over expression system. Based on these observations we propose that N. gonorrhoeae employs specific intracellular signaling receptors that respond to intracellular gonococci and or their ligands, resulting in proinflammatory responses that contribute to N. gonorrhoeae induced inflammation in vivo. To test this hypothesis we propose the following aims: 1. To define the role of NLR signaling receptors (clAP2, N0D1, and N0D2) in N. gonorrhoeae induction of proinflammatory cytokines in human epithelial cells and macrophages;2. To define the role of NLR signaling receptors (clAP2, N0D1, and N0D2) in N. gonorrhoeae induction of proinflammatory cytokines in murine epithelial cells and macrophages;and 3. To define the role of NLRs in N. gonorrhoeae induced inflammatory responses in a mouse model.
There are gaps in our knowledge regarding specific details of the interactions between N. gonorrhoeae and the innate immune response that results in inflammatory disease. This study will use novel in vitro and in vivo approaches to define the mechanisms that control host signaling in response to N. gonorrhoeae Improved understanding of the mechanisms driving innate immune recognition of pathogens and the roles of specific cytokines and the factors that trigger their expression will provide a promising avenue for novel therapies for this bacterially induced inflammatory disease.
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