HIV通过SOCS1/3蛋白调控TLR通路及相关细胞因子促进Mtb感染的机制

CD4+T细胞数量减少引起的免疫功能缺陷不能完全解释HIV感染促进结核分枝杆菌（Mtb）感染。我们前期研究发现HIV感染可导致巨噬细胞SOCS1/3表达上调，而SOCS1/3是Mtb感染相关的天然免疫TLR通路和多种细胞因子通路的调控因子，很可能在HIV促进Mtb感染中发挥重要作用。本项目通过检测HIV、Mtb、HIV/Mtb感染人群和对照人群中，巨噬细胞SOCS1/3和TLR2/4/9信号通路下游Mtb感染相关细胞因子的表达差异，分析其与Mtb感染的关系；采用巨噬细胞-HIV-Mtb模型、SOCS基因沉默和过表达技术，研究HIV感染引起的SOCS1/3表达如何影响TLR和Mtb感染关键细胞因子通路，进而促进Mtb感染。本研究首次从SOCS1/3蛋白和天然免疫TLR通路入手，在人群、细胞、分子水平揭示HIV/Mtb双重感染的分子机制，为HIV/Mtb双重感染提供基于天然免疫的防治新思路。

The deficiency of adaptive immunity due to deletion of CD4+T cells by HIV infection cannot fully explain the phenomenon that HIV promotes Mtb infection. Our preliminary research showed that HIV infection can result in increased expression of SOCS1/3 proteins in macrophages. SOCS1/3 are regulatory factors of Mtb infection-related innate immune TLR pathways as well as many cytokine pathways，which may play an important role in HIV promoting Mtb infection. This study aims to explore how SOCS1/3 affect the innate immune pathways and Mtb infection-related cytokine pathways, and then promote Mtb infection. We will detect the expression levels of SOCS1/3 and downstream cytokines of TLR2/4/9 in human macropahges and find the differences among HIV-infected, Mtb- infected, HIV/Mtb co-infected patients and control population as well as the associations of these factors to Mtb infection. We will also utilize macrophages-HIV-Mtb system and use gene silencing and over-expression techniques to determine the role of HIV-induced SOCS1/3 expression in regulating TLR2/4/9 pathways as well as pathways of Mtb infection-related cytokines and subsequently promoting Mtb infection of macrophages. This study, for the first time, from the perspective of the SOCS proteins and innate immune TLR pathways, will explore the mechanism(s) of HIV/Mtb co-infection at population, cellular and molecular levels, and provide innate immunity-based strategy to prevent and therapy HIV/Mtb co-infection.