Viperin抑制IRAK1-TRAF6-TAK1信号通路介导的巨噬细胞功能及抗结核免疫的机制研究

Viperin是干扰素刺激基因之一，能调节病毒感染及宿主免疫反应，但其在结核分枝杆菌（Mtb）感染免疫中作用未知。我们前期研究表明，Viperin在结核（TB）患者组织中表达上调；Viperin缺陷（Rsad2-/-）小鼠较WT小鼠肺部细菌量减少、NO增加；沉默Viperin能诱导巨噬细胞（Mϕ）向M1型分化、促进炎性因子和NO的产生、抑制Mtb复制；另外，Viperin与IRAK1和TAK1作用，抑制IRAK1与TRAF6的结合。据此提出假说：Viperin通过IRAK1-TRAF6-TAK1信号通路影响Mϕ功能调控Mtb感染。拟进一步：①利用细胞和Rsad2-/-小鼠模型，研究Viperin调控IRAK1-TRAF6-TAK1通路与Mϕ功能介导的TB感染免疫反应的机制；②通过临床样本探究Viperin调节Mϕ功能的通路与TB病变的关系。这将为靶向Viperin治疗TB提供新的依据。

Viperin is one of interferon stimulating genes, which can regulate viral infection and host immune response. However, its function in immune response to Mycobacterium tuberculosis (Mtb) infection remains unknown. Our previous studies have demonstrated that viperin expression was up-regulated in the tissues of TB patients. Viperin deficient (Rsad2-/-) mice exerted decreased Mtb infection and increased production of NO in lungs than that in wild type (WT) mice. Viperin silencing could induce macrophages (Mϕ) to differentiate into M1 type, promote inflammatory cytokine and NO production, and inhibit Mtb replication. In addition, Viperin interacted with IRAK1 and TAK1 to inhibit the interaction of IRAK1 and TRAF6. Based on these findings, we hypothesis that Viperin influences Mϕ function to regulate Mtb infection through IRAK1-TRAF6-TAK1 signaling pathway. We intend to further investigate the mechanisms of Viperin in regulating immune response and Mϕ function to Mtb infection through IRAK1-TRAF6-TAK1 pathway by using Rsad2-/- mice and cell culture models. Furthermore, we will analyze clinical samples to explore the relationship between Viperin regulating pathways of Mϕ function and pathological process of TB. This study will provide a new basis for targeting Viperin as a therapeutic strategy for TB treatment.