TLR2 and the Tubercle Granuloma

TLR2 和结节肉芽肿

基本信息

项目摘要

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. Preliminary gene expression studies point to the role of TLR2-induced matrix metaloproteinases in regulating granuloma maturation. The following specific hypotheses will be tested in the proposal: i) TLR2-induced MMPs regulate granuloma maturation; ii)TLR2 is essential for macrophage control of Mtb replication and containment within the granuloma; iii) TLR2 induces Tregs which operate primarily as inhibitors of lung immune pathology but not as inhibitors of macrophage antimicrobial responses; iv) TLR2-triggers two distinct signaling pathways for the induction of pro- and anti-inflammatory cytokine production within Mtb- infected macrophages, and v) 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.
在这个应用中,我们将探索这样的假设,即Toll样受体2(TLR2)是控制结节肉芽肿的保护性和病理学特征的主要调节因子。这一假设建立在我们实验室的新发现之上。以前我们曾报道TLR9和TLR2在结核分枝杆菌感染的树突状细胞(DC)中分别诱导促炎和抗炎细胞因子,而TLR2在感染的巨噬细胞中既诱导促炎细胞因子又诱导抗炎细胞因子。基于这些观察,一个合理的预测是,在结核分枝杆菌感染过程中,TLR2引发的先天抗炎反应可能控制Th1效应器和记忆性T细胞的激活。与预期相反,我们发现TLR2的缺失并不影响结核分枝杆菌气溶胶感染后产生的Th1效应器反应的大小,也不影响对结核分枝杆菌攻击的Recall Th1记忆免疫的诱导。然而,TLR2缺失对寄主抗性的影响表现在肉芽肿水平。感染TLR2KO小鼠的肺部表现出与FoxP3[+]T调节细胞(Tregs)向肺内渗透减少相关的炎症增强,而感染WT的小鼠的肺部炎症已经消退,并有小而致密的肉芽肿。已有研究表明,Treg能抑制宿主对持久性病原体的抗菌反应。令人惊讶的是,尽管没有Tregs,但与感染WT的小鼠相比,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的丧失,这表明到目前为止,TLR2在控制体内肉芽肿的抗微生物反应中的作用被低估。初步的基因表达研究指出TLR2诱导的基质金属蛋白酶在调节肉芽肿成熟中的作用。 该提案将检验以下特定假设:i)TLR2诱导的MMPs调节肉芽肿成熟;ii)TLR2对于巨噬细胞控制Mtb复制和控制肉芽肿内的Mtb至关重要;iii)TLR2诱导Tregs,其主要作用是抑制肺免疫病理,而不是巨噬细胞抗菌反应的抑制;iv)TLR2-触发两条不同的信号通路,诱导Mtb感染的巨噬细胞产生促炎和抗炎细胞因子,以及v)信号通路相互交叉调节,Mtb可以操纵这两条通路以获得自身的利益。这些拟议研究的集体发现将提供对TLR2触发的结节肉芽肿信号通路的见解,以及在治疗中操纵它们的独特方式。

项目成果

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Padmini Salgame其他文献

Padmini Salgame的其他文献

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{{ truncateString('Padmini Salgame', 18)}}的其他基金

Animal models and related services (AMRS) core
动物模型和相关服务(AMRS)核心
  • 批准号:
    10793866
  • 财政年份:
    2023
  • 资助金额:
    $ 17.99万
  • 项目类别:
One-carbon metabolism and immune cell function in tuberculosis
结核病中的一碳代谢和免疫细胞功能
  • 批准号:
    10719273
  • 财政年份:
    2023
  • 资助金额:
    $ 17.99万
  • 项目类别:
Immune Determinants of the Course of Mycobacterium tuberculosis infection and Disease
结核分枝杆菌感染和疾病过程的免疫决定因素
  • 批准号:
    10493277
  • 财政年份:
    2021
  • 资助金额:
    $ 17.99万
  • 项目类别:
Immune Determinants of the Course of Mycobacterium tuberculosis infection and Disease
结核分枝杆菌感染和疾病过程的免疫决定因素
  • 批准号:
    10271649
  • 财政年份:
    2021
  • 资助金额:
    $ 17.99万
  • 项目类别:
Immune Determinants of the Course of Mycobacterium tuberculosis infection and Disease
结核分枝杆菌感染和疾病过程的免疫决定因素
  • 批准号:
    10665030
  • 财政年份:
    2021
  • 资助金额:
    $ 17.99万
  • 项目类别:
Program in Infection, Immunity and Inflammation
感染、免疫和炎症项目
  • 批准号:
    9924471
  • 财政年份:
    2016
  • 资助金额:
    $ 17.99万
  • 项目类别:
TLR2 and the Tubercle Granuloma
TLR2 和结节肉芽肿
  • 批准号:
    8231291
  • 财政年份:
    2011
  • 资助金额:
    $ 17.99万
  • 项目类别:
TLR2 and the Tubercle Granuloma
TLR2 和结节肉芽肿
  • 批准号:
    8714524
  • 财政年份:
    2011
  • 资助金额:
    $ 17.99万
  • 项目类别:
TLR2 and the Tubercle Granuloma
TLR2 和结节肉芽肿
  • 批准号:
    8616331
  • 财政年份:
    2011
  • 资助金额:
    $ 17.99万
  • 项目类别:
TLR2 and the Tubercle Granuloma
TLR2 和结节肉芽肿
  • 批准号:
    8032716
  • 财政年份:
    2011
  • 资助金额:
    $ 17.99万
  • 项目类别:

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