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

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.

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。

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信号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。本课题采用人群研究和体外研究相结合的方法，探讨了HIV感染引起的SOCS1/3表达如何影响TLR2和Mtb感染关键细胞因子信号通路促进Mtb感染。以HIV-1单感染组、Mtb单感染组、HIV-1/Mtb双重感染组、健康对照组共4组人群为研究对象，检测各组人群中SOCS1/3、TLR2/4/9通路下游Mtb感染相关细胞因子，研究HIV-1/MTB感染与巨噬细胞SOCS1/3、TLR2/4/9通路下游Mtb感染相关细胞因子表达的相关性研究。结果发现，HIV-1感染组外周血PBMCs中SOCS3、TLR9、IL-6和IL-10的表达量高于健康对照组，Mtb单感染组外周血PBMCs中IFN-γ、IL-1β、IL-12均高于健康对照组。体外研究以巨噬细胞-HIV-Mtb感染模型为基础，明确了HIV-1感染能够上调巨噬细胞SOCS1/SOCS3的表达，高表达的SOCS1/SOCS3负反馈调控巨噬细胞天然免疫TLR2信号通路，导致下游IFN-γ（巨噬细胞M1型极化诱导剂之一）表达下调，抑制THP-1巨噬细胞向M1型极化，使巨噬细胞免疫协同作用遭到破坏，导致HIV复制和Mtb感染的增加。同时，高表达的SOCS1/SOCS3，可以诱导巨噬细胞IL-6表达升高，IL-6一方面是促结核感染因子，另一方面可以诱导巨噬细胞向M2极化、抗炎症的方向发展（IL-10升高），利于Mtb感染。本项目从天然免疫角度出发，研究细胞因子负调控蛋白SOCS1/SOCS3分子对巨噬细胞TLR信号通路以及巨噬细胞极化的作用，初步阐明了HIV-1感染能够上调巨噬细胞SOCS1和SOCS3的表达，抑制细胞天然免疫TLR2信号通路，导致下游IFN-γ表达下调、IL-6和IL-10表达上调，进而可能影响巨噬细胞极化过程，从而促进Mtb的感染。研究结果将有助于更好地理解HIV-1促进Mtb感染的自然过程，为调整HIV/Mtb双重感染人群治疗方案提供指导。