TLR2 Regulation of Host Immune Response in TB

描述(由申请人提供)：由肺部病原体结核分枝杆菌(结核分枝杆菌)引起的死亡率和发病率仍然高得惊人。阐明抑制宿主Th1免疫的机制不仅对于理解结核病的免疫病理学很重要，而且对于更好地理解结核分枝杆菌是如何为了自身生存而篡夺宿主的这些调节制衡是必要的。这一应用的重点是检查宿主中由控制Th1效应和记忆反应的DC中的TLR2信号激活的免疫抑制通路。可以激活几个互补的调节电路，它们一起调节主机免疫，从而在对主机的损害最小的情况下实现保护。在研究Mtb与小鼠骨髓来源的巨噬细胞和DC的相互作用时，观察到DCs在Mtb感染后释放大量的白介素12，而巨噬细胞的分泌有限。此外，Mtb诱导的DC中p40启动子的重塑和IL-12的释放是Toll样受体(TLR)9依赖的，而巨噬细胞则依赖TLR2。然而，在这两种细胞类型中，免疫抑制/抗炎细胞因子IL-10的释放主要依赖于TLR2。总之，这些发现表明，与巨噬细胞不同，DC能够通过更有效的TLR9途径诱导IL-12基因，同时使用TLR2途径诱导IL-10。DC对IL-12和IL-10的不同TLR使用对宿主的进化优势是什么？假设DC对TLR的分离使用是一种协调和调节两种相反的细胞因子表达的手段，从而使宿主能够在保护和病理之间取得平衡。这一假设将在以下两个目标中得到检验：Mtb和TLR2相互作用所释放的固有IL-10促进DC的“替代激活”，并抑制其Th1激活潜力。AIM2.Mtb和TLR2相互作用所释放的固有IL-10促进“调节性DC”激活T调节性细胞以控制Th1激活的幅度。长期目标是更好地了解Th1免疫在宿主中是如何调节的。每年新增结核病病例800万例，约占发展中国家所有死亡病例的7%，占所有可避免的成人死亡病例的26%。结核病确实构成了全球卫生紧急情况。这项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.