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

Guoliang Zhang, Nicole A. deWeerd, Sebastian A. Stifter, Lei Liu, Boping Zhou, Wenfei Wang, Yiping Zhou, Binwu Ying, Xuejiao Hu, Antony Y. Matthews, Magda Ellis, James A. Triccas, Paul J. Hertzog, Warwick J. Britton, Xinchun Chen () and Carl G. Feng ()
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Guoliang Zhang: Guangdong Medical University
Nicole A. deWeerd: Hudson Institute of Medical Research
Sebastian A. Stifter: The University of Sydney
Lei Liu: Guangdong Medical University
Boping Zhou: Guangdong Medical University
Wenfei Wang: Guangdong Medical University
Yiping Zhou: Sun Yet-sen University
Binwu Ying: Sichuan University
Xuejiao Hu: Sichuan University
Antony Y. Matthews: Hudson Institute of Medical Research
Magda Ellis: Tuberculosis Research Program, Centenary Institute
James A. Triccas: Tuberculosis Research Program, Centenary Institute
Paul J. Hertzog: Hudson Institute of Medical Research
Warwick J. Britton: Tuberculosis Research Program, Centenary Institute
Xinchun Chen: Guangdong Medical University
Carl G. Feng: Guangdong Medical University

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02611-z

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