Receptors Involved in Microglial Responses to S. aureus

描述(由申请人提供)：获得性免疫对于有效辐射感染性病原体是必不可少的，尽管适应性免疫反应失调也可能导致自身免疫和慢性炎症性疾病的诱导。Toll样受体通过促进抗原提呈细胞和T细胞之间的相互作用，在启动获得性免疫中起着至关重要的作用。关于CMS感染性疾病，我们的实验室最近报道，在金黄色葡萄球菌诱导的脑脓肿模型中，TLR2的丢失导致IL-17的高表达，IL-17是一种与抗细菌反应和自身免疫有关的细胞因子。此外，我们的初步研究表明，TLR2依赖信号的丢失导致TLR2 KO小鼠中CD4+和CD8+T细胞流入脑脓肿的增加，从而导致Th1到Th17的偏向。尽管TLR2和IL-17已被证明在单独的抗细菌免疫反应中发挥关键作用，但据我们所知，还没有人研究TLR2与Th17细胞生成/扩增的相互关系。此外，尽管最近的报道揭示了Th17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，但研究TLR2和Th17细胞之间的相关性的研究尚未在任何中枢神经系统炎症性疾病模型中进行。这一提议的总体假设是，TLR2依赖信号的丢失导致Th17反应被夸大，这是一种补偿机制，由于IL-17能够诱导大量中性粒细胞趋化因子的表达，从而有效地将中性粒细胞招募到脑脓肿中。这种夸大的Th17反应将有助于确保获得足够的中性粒细胞数量，以有效地控制中枢神经系统的细菌负荷。为了解决这一假说，将解决以下具体目标：1)描述脓肿相关抗原提呈细胞信号(S)导致TLR2KO小鼠Th17T细胞发育：2)通过检测TLR2KO小鼠T细胞浸润的激活状态和金黄色葡萄球菌超抗原反应性T细胞在疾病中的作用，研究TLR2与脑脓肿获得性免疫反应的相互作用；3)确定TLR2 KO小鼠脑脓肿中IL-17的表达升高是否代表了一种代偿机制，通过使用含有IL-17受体(IL-17R)或IL-17的可溶性形式的重组腺病毒载体分别中和和过度表达IL-17在脑脓肿环境中获得足够的抗细菌免疫。这些研究应该为IL-17在脑脓肿发展过程中的功能作用提供关键的见解，以及针对IL-17的表达是否代表着未来人类疾病管理的可行治疗选择，以实现加速细菌从中枢神经系统的清除，同时将对周围组织的病理损害降至最低，这是该疾病的一个标志。

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.