I型IFN信号通路在人结核病发生发展中的作用及其机制研究

The previous finding showed that type I IFN detrimentally affected the outcome of M.tuberculosis infection in mice through inhibiting anti-M.tb response and accelerating the inflammatory pathogenesis injury. Due to the inherent limitations of clinical investigation, the role of type I IFN produced in human Tuberculosis is less clear. We found that type I IFN production, especially IFN-β, is associated with virulence of M.tb, and only virulent mycobacteria with a competent ESX-1 secretion system could induce IFN-β production. Furthermore, IFNAR1 gene rs72552343 allele deletion leads to the defection of type I IFN signal pathway, and it was associated with decreased Tuberculosis susceptibility. It showed type I IFN may play the immune pathogenesis role in human Tuberculosis similar to the mice. Naturally IFNAR1 gene deletion provides a new model to explore the role of type I IFN in human Tuberculosis similar to the gene knockout mice. In this study, we plan to explore the influence and mechanism of IFNAR1 gene deletion on anti- M.tb response in human macrophage in vitro, and then we explore the role of type I IFN and IFNAR1 genotypes in TB through IFN-α treatment cohort.

已有研究表明，I型干扰素抑制小鼠抗结核免疫，加重小鼠肺结核炎症病理损伤，在小鼠肺结核发生中起着病理性作用。由于临床研究的局限性，目前尚不清楚I型干扰素在人结核病的作用。我们的新近研究发现，1）巨噬细胞I型干扰素（IFN-β）的分泌与感染的结核菌毒力密切相关，只有ESX-1完整的有毒株才能细胞分泌IFN-β；2）I型干扰素受体INFAR1的基因外显子SNP rs72552343等位基因缺失导致其功能缺陷，而携带基因缺失型SNP的 个体结核病发生风险显著降低；提示I型干扰在人结核病中可能起着与小鼠肺结核类似的病理性作用。自然发生INFAR1基因缺失提供了类似小鼠基因敲除的模型，使探讨I型干扰素在人结核病中的作用成为可能。本项目拟在体外实验探讨IFNAR1基因缺失对巨噬细胞抗结核免疫的影响及其发生的具体机制，进而通过IFNAR1基因型/I型干扰素干预的队列研究I型干扰素在结核病发生发展中的作用。