TLR2 Regulation of Host Immune Response in TB

描述（由申请人提供）：由肺病原体结核分枝杆菌（Mtb）引起的死亡率和发病率仍然高得惊人。阐明削减宿主Th 1免疫力的机制不仅对理解结核病的免疫病理学很重要，而且对于更好地了解毒性结核分枝杆菌如何篡夺宿主中的这些调节制衡以维持自身生存也是必要的。本申请的重点是检查宿主中由DCs中的TLR 2信号传导激活的免疫抑制途径，所述DCs控制Th 1效应器和记忆应答。可以激活几个互补的调节回路，其一起调节宿主免疫力，使得在对宿主的损伤最小的情况下实现保护。在检查Mtb与鼠骨髓衍生的巨噬细胞和DC的相互作用的研究中，观察到响应于Mtb感染，DC释放大量的白细胞介素（IL）-12，而巨噬细胞中的分泌是有限的。此外，Mtb诱导的p40启动子重构和DC中IL-12的释放是Toll样受体（TLR）9依赖性的，而在巨噬细胞中则相反。然而，免疫抑制/抗炎细胞因子IL-10的释放在两种细胞类型中主要是TLR 2依赖性的。总的来说，这些发现表明，与巨噬细胞不同，DC能够参与更有效的TLR 9途径来诱导IL-12基因，同时使用TLR 2途径来诱导IL-10。树突状细胞对TLR的不同利用对宿主产生IL-12和IL-10有什么进化优势？假设DC对TLR使用的分离是协调和调节两种相反细胞因子表达的手段，使得宿主可以实现保护和病理之间的平衡。该假设将在以下两个目标中进行测试：目标1。响应于Mtb和TLR 2相互作用而释放的天然IL-10促进DC的“替代活化”并抑制其Th 1活化潜力。目标2。响应于Mtb和TLR 2相互作用而释放的天然IL-10促进“调节性DC”，其激活调节性T细胞以控制Th 1激活的幅度。长期目标是更好地了解Th 1免疫在宿主中的调节方式。在发展中国家，每年新发800万例结核病，约占所有死亡人数的7%，占所有可避免的成人死亡人数的26%。结核病确实构成了全球卫生紧急情况。该提案产生的数据将为制造更好的结核病疫苗提供新的战略。

DESCRIPTION (provided by applicant): Mortality and morbidity caused by the pulmonary pathogen Mycobacterium tuberculosis (Mtb) remains alarmingly high. Elucidating the mechanisms that curtail host Th1 immunity is not only important for understanding immunopathology in TB, but is also necessary to gain a better appreciation for how virulent Mtb usurp these regulatory checks and balances in the host for their own survival. The focus of this application is to examine the immunosuppressive pathways activated in the host by TLR2 signaling in DCs that control Th1 effector and memory responses. Several complementary regulatory circuits may be activated that together modulate host immunity such that protection is achieved with minimal damage to the host. In studies examining Mtb interaction with murine bone marrow-derived macrophages and DCs, it was observed that in response to Mtb infection, DCs released abundant Interleukin (IL)-12, while secretion was limited in macrophages. Furthermore, Mtb-induced remodeling at the p40 promoter and IL-12 release in DCs was Toll-like receptor (TLR) 9-dependent, and in contrast TLR2 dependent in macrophages. The release of the immunosuppressive/anti-inflammatory cytokine IL-10, however, was predominantly TLR2-dependent in both cell types. Collectively, these findings demonstrate that, unlike macrophages, DCs are able to engage the more efficient TLR9 pathway for IL-12 gene induction, while using the TLR2 pathway for induction of IL-10. What is the evolutionary advantage to the host of the differential TLR usage by DCs for IL-12 and IL-10 production? It is hypothesized that the segregation of TLR usage by DCs is a means to coordinate and regulate the expression of two opposing cytokines such that the host can achieve a balance between protection and pathology. The hypothesis will be tested in the following two aims: Aim1. Innate IL-10 released in response to Mtb and TLR2 interaction promotes "alternative activation" of DCs and dampens their Th1 activation potential. Aim2. Innate IL-10 released in response to Mtb and TLR2 interaction promotes "regulatory DCs" that activate T regulatory cells to control the magnitude of Th1 activation. The long-term goal is to gain a better insight into how Th1 immunity is regulated in the host. Eight million new cases of tuberculosis occur each year, accounting for approximately 7% of all deaths and 26% of all avoidable adult deaths in developing countries. TB truly constitutes a global health emergency. Data generated from this proposal will provide new strategies for making better vaccines against Tuberculosis.