TLR2 and the Tubercle Granuloma

在本申请中，我们将探讨Toll样受体2（TLR 2）是主调节因子的假设 控制结核肉芽肿的保护性和病理学特征。这个假设建立在 我们实验室里的新发现。以前，我们曾报道TLR 9和TLR 2诱导促凋亡和凋亡。 抗炎细胞因子，分别在M.结核病（Mtb）感染的树突状细胞（DC），而 TLR 2在感染的巨噬细胞中诱导促炎细胞因子和抗炎细胞因子。合理 基于这些观察，预测在Mtb感染期间， 由TLR 2触发的信号转导可能控制Th 1效应和记忆T细胞活化的大小。违反 预期，我们发现TLR 2的缺乏并不影响Th 1效应反应的大小 产生后气雾剂感染结核分枝杆菌或诱导回忆Th 1记忆免疫反应 Mtb挑战然而，TLR 2缺失对宿主抗性的后果在细胞中表现出来。 肉芽肿的水平。TLR 2KO小鼠感染的肺表现出增强的炎症相关性。 FoxP 3+调节性T细胞（TCFs）向肺中的浸润减少，而来自感染WT的肺 动物的炎症已消退，并有小而致密的肉芽肿。已经证明， 阻碍宿主对持久性病原体的抗微生物反应。令人惊讶的是，尽管没有 来自慢性感染的TLR 2KO小鼠的肺表现出增强的细菌负荷和细胞因子的损失。 与感染的WT小鼠相比，肉芽肿的完整性表明迄今为止未被充分认识的作用， TLR 2在肉芽肿中控制体内抗菌反应。 在该提案中将测试以下具体假设：i）TLR 2对于巨噬细胞是必需的。 控制肉芽肿内的Mtb复制和遏制; ii）TLR 2诱导TbR，其在肉芽肿内起作用， 主要作为肺免疫病理学抑制剂，但不作为巨噬细胞抗菌剂抑制剂 iii）TLR 2-触发两种不同的信号传导途径，用于诱导促炎和抗炎反应。 Mtb感染的巨噬细胞内的细胞因子产生，和iv）信号传导途径交叉调节每个 其他人和Mtb可以操纵这些途径以获得自己的利益。从拟议的调查结果中得出的集体结论是， 研究将提供对结核肉芽肿中TLR 2触发的信号通路的深入了解， 这些方法可以被用于治疗。

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.