IFNAR1 中的脯氨酸缺失会损害 IFN 信号传导，并导致人类对结核病的抵抗力增强。

A proline deletion in IFNAR1 impairs IFN-signaling and underlies increased resistance to tuberculosis in humans.

机构信息

Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical University, 518112, Shenzhen, Guangdong, China.

Immunology and Host Defense Group, Department of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia.

出版信息

Nat Commun. 2018 Jan 8;9(1):85. doi: 10.1038/s41467-017-02611-z.

Type I interferons (IFN), best known for their anti-viral functions, have been shown to impair host resistance to intracellular bacteria in mice. However, the precise role of type I IFN signaling in bacterial infection in humans is unclear. Here, we show that genetic variation in the human IFNAR1 gene is associated with decreased susceptibility to tuberculosis and an increased risk of viral hepatitis in Chinese populations. Receptor mutagenesis and cell signaling studies establish that the IFNAR1 mutation corresponding to a proline deletion in the hinge region of the membrane-proximal domain of IFNAR1 decreases the binding affinity of IFNAR1 to IFN-β, impeding type I IFN signaling. Our findings suggest that IFNAR1 signaling underlies an increased risk of tuberculosis in humans and reveals a function for the IFNAR1 inter-domain region in cytokine-cytokine receptor interaction and signal transduction.

I 型干扰素（IFN）以其抗病毒功能而闻名，已被证明会损害宿主对小鼠体内细菌的抵抗力。然而，I 型 IFN 信号在人类细菌感染中的确切作用尚不清楚。在这里，我们表明，人类 IFNAR1 基因的遗传变异与中国人中结核病易感性降低和病毒性肝炎风险增加有关。受体突变和细胞信号研究确立了与 IFNAR1 膜近端结构域铰链区脯氨酸缺失相对应的 IFNAR1 突变会降低 IFNAR1 与 IFN-β的结合亲和力，从而阻碍 I 型 IFN 信号。我们的研究结果表明，IFNAR1 信号是人类结核病风险增加的基础，并揭示了 IFNAR1 结构域间区域在细胞因子-细胞因子受体相互作用和信号转导中的功能。