Receptors Involved in Microglial Responses to S. aureus

描述（由申请人提供）：适应性免疫对于有效消灭感染性病原体是必不可少的，尽管失调的适应性免疫应答也可能导致诱导自身免疫性疾病和慢性炎性疾病。Toll样受体（TLR）通过促进抗原呈递细胞（APC）和T细胞之间的相互作用而对启动适应性免疫至关重要。关于CMS感染性疾病，我们的实验室最近描述了S.金黄色葡萄球菌诱导的脑脓肿模型导致IL-17的表达增加，IL-17是一种与抗菌应答以及自身免疫有关的细胞因子。此外，我们的初步研究已经证明，TLR 2依赖性信号的丢失导致CD 4+和CD 8 + T细胞向脑细胞中的流入增加，并导致TLR 2 KO小鼠中Th 1向Th 17的偏倚。尽管事实上TLR和IL-17已被证明在抗细菌免疫应答中单独发挥关键作用，但据我们所知，还没有人研究TLR 2和Th 17细胞的产生/扩增之间的相互关系。此外，尽管最近的报道已经揭示了Th 17细胞在实验性自身免疫性脑脊髓炎（EAE）的免疫发病机制中的致病作用，但尚未在任何CNS炎性疾病模型中进行检查TLR 2和Th 17细胞之间的关联的研究。该提案的总体假设是，TLR 2依赖性信号传导的丧失导致Th 17反应过度，由于IL-17能够诱导多种中性粒细胞的表达，Th 17反应作为一种补偿机制有效地将中性粒细胞招募到脑脓肿中。化学引诱物。这种夸大的Th 17应答将用于确保获得足够的中性粒细胞数量以有效地控制CNS细菌负荷。为了解决这一假设，将解决以下具体目标：1）描绘源自导致TLR 2 KO小鼠中Th 17发育的脑脓肿相关抗原呈递细胞的信号; 2）通过检查TLR 2 KO小鼠中T细胞浸润的活化状态和S.疾病中的金黄色葡萄球菌超抗原反应性T细胞;和3）确定TLR 2 KO小鼠脑水肿中升高的IL-17表达是否代表通过使用携带可溶形式的IL-17受体（IL-17 R）或IL-17的重组腺病毒构建体分别中和和过表达IL-17来实现足够的抗细菌免疫的补偿机制，在脑脓肿的环境中。这些研究应提供关键的见解，IL-17在脑脓肿发展过程中的功能作用，以及靶向IL-17表达是否将代表未来人类疾病管理的可行治疗选择，以实现加速细菌从CNS中清除，同时最大限度地减少对周围组织的病理损伤，这是疾病的标志。

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.