TLR2 and the Tubercle Granuloma

在这个应用中，我们将探索Toll样受体2(TLR2)是主调节因子的假设 控制结节肉芽肿的保护性和病理学特征。这一假设是建立在 我们实验室的新发现。以前我们已经报道过TLR9和TLR2诱导前和 结核分枝杆菌(Mtb)感染的树突状细胞(DC)中的抗炎细胞因子，而 TLR2在感染的巨噬细胞中诱导促炎和抗炎细胞因子。一个合理的 基于这些观察的预测是，在结核分枝杆菌感染期间，先天的抗炎反应 由TLR2触发可能控制Th1效应器和记忆性T细胞的激活。与…相反 预期，我们发现TLR2的缺失并不影响Th1效应器反应的大小 在气溶胶感染结核分枝杆菌或诱导Recall Th1记忆免疫应答后产生 参加MTB挑战赛。然而，TLR2缺失对寄主抗性的影响表现在 肉芽肿的程度。TLR2KO小鼠感染的肺部表现出与炎症相关的增强 随着FoxP3+T调节细胞(Tregs)对肺的渗透减少，而感染WT的肺 动物的炎症已经消退，有小而致密的肉芽肿。特雷格已经被证明是 阻碍宿主对持久性病原体的抗菌素反应。令人惊讶的是，尽管没有 Tregs，慢性感染TLR2KO小鼠的肺显示出更多的细菌负荷和 肉芽肿完整性与感染的WT小鼠的比较表明，迄今为止未被认识到的 TLR2在控制肉芽肿体内抗菌反应中的作用。 该提案将检验以下具体假设：i)TLR2对巨噬细胞是必不可少的 控制结核分枝杆菌复制和控制肉芽肿内；ii)TLR2诱导Tregs 主要作为肺免疫病理的抑制剂，而不是巨噬细胞抗菌剂的抑制剂 反应；iii)TLR2-触发两条不同的信号通路，诱导促炎和抗炎 结核分枝杆菌感染的巨噬细胞内细胞因子的产生，以及iv)信号通路相互交叉调节 Other和Mtb可以为自己的利益操纵道路。建议的综合调查结果 研究将提供对TLR2触发的信号通路在结节肉芽肿和独特的 它们可以在治疗上被操纵的方式。

In this application we will explore the hypothesis that Toll-like receptor 2 (TLR2) is the master regulator controlling both protective and pathologic features of the tubercle granuloma. The hypothesis builds on novel findings made in our laboratory. Previously we had reported that TLR9 and TLR2 induce pro- and anti-inflammatory cytokines, respectively, in M. tuberculosis (Mtb)-infected dendritic cells (DCs), while TLR2 induces both pro- and anti-inflammatory cytokines in infected macrophages. A reasonable prediction, based on these observations, is that during Mtb infection the innate anti-inflammatory response triggered by TLR2 may control the magnitude of Th1 effector and memory T cell activation. Contrary to expectation, we found that the absence of TLR2 did not affect the magnitude of the Th1 effector response generated following aerosol infection with Mtb or the induction of recall Th1 memory immunity in response to Mtb challenge. However, the consequence of TLR2 absence to host resistance was manifested at the level of the granuloma. The infected lungs of TLR2KO mice exhibited enhanced inflammation associated with reduced infiltration of FoxP3+ T regulatory cells (Tregs) into the lung, while lungs from infected WT animals had resolved their inflammation and had small, compact granulomas. Tregs have been shown to thwart host antimicrobial responses against persistent pathogens. Surprisingly, despite the absence of Tregs, lungs from chronically-infected TLR2KO mice exhibited enhanced bacterial burden and loss of granuloma integrity in comparison with infected WT mice indicating a hitherto under-appreciated role for TLR2 in controlling antimicrobial responses in vivo in the granuloma. The following specific hypotheses will be tested in the proposal: i)TLR2 is essential for macrophage control of Mtb replication and containment within the granuloma; ii) TLR2 induces Tregs which operate primarily as inhibitors of lung immunopathology but not as inhibitors of macrophage antimicrobial responses; iii) TLR2-triggers two distinct signaling pathways for the induction of pro- and anti-inflammatory cytokine production within Mtb-infected macrophages, and iv) the signaling pathways cross-regulate each other and Mtb can maneuver the pathways to its own benefit. The collective findings from the proposed studies will provide insights into TLR2-triggered signaling pathways in the tubercle granuloma and unique ways in which they can be manipulated therapeutically.