Receptors Involved in Microglial Responses to S. aureus

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DESCRIPTION (provided by applicant): Adaptive immunity is essential for the efficient eradiation of infectious pathogens, although dysregulated adaptive immune responses may also lead to the induction of autoimmune and chronic inflammatory diseases. Toll-like receptors (TLRs) are critical for the initiation of adaptive immunity by facilitating interactions between antigen-presenting cells (APCs) and T cells. With regard to CMS infectious disease, our laboratory has recently described that the loss of TLR2 in the S. aureus-induced brain abscess model leads to the heightened expression of IL-17, a cytokine that has been implicated in anti-bacterial responses as well as autoimmunity. In addition, our preliminary studies have demonstrated that the loss of TLR2-dependent signals leads to the elevated influx of CD4+ and CD8+ T cells into brain abscesses and a resultant Th1 to Th17 bias in TLR2 KO mice. Despite the fact that TLRs and IL-17 have been shown to play pivotal roles in anti-bacterial immune responses individually, to our knowledge, no one has yet examined the interrelationship between TLR2 and the generation/expansion of Th17 cells. Furthermore, although recent reports have revealed a pathogenic role for Th17 cells in the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE), studies examining the association between TLR2 and Th17 cells have not yet been performed in any CNS inflammatory disease model. The overall hypothesis of this proposal is that the loss of TLR2-dependent signaling leads to an exaggerated Th17 response, which functions as a compensatory mechanism to effectively recruit neutrophils into brain abscesses due to the ability of IL-17 to induce the expression of numerous neutrophil chemoattractants. This exaggerated Th17 response would serve to ensure that sufficient neutrophil numbers are achieved to effectively contain CNS bacterial burdens. To address this hypothesis, the following specific aims will be addressed: 1) to delineate the signal(s) derived from abscess-associated antigen presenting cells leading to Th17 development in TLR2 KO mice; 2) to investigate the interactions between TLR2 and the adaptive immune response in brain abscess by examining the activation status of T cell infiltrates in TLR2 KO mice and the role of S. aureus superantigen-reactive T cells in disease; and 3) to determine whether elevated IL-17 expression in brain abscesses of TLR2 KO mice represents a compensatory mechanism to achieve sufficient anti-bacterial immunity through the use of recombinant adenoviral constructs harboring a soluble form of the IL-17 receptor (IL-17R) or IL-17 to neutralize and over-express IL-17, respectively, within the brain abscess milieu. These studies should provide critical insights into the functional role of IL-17 during brain abscess development and whether targeting IL-17 expression would represent a viable therapeutic option for future disease management in humans to achieve accelerated bacterial clearance from the CNS while minimizing pathological damage to surrounding tissue that is a hallmark of the disease.