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

Author

Listed:
  • Guoliang Zhang

    (Guangdong Medical University
    The University of Sydney
    Tuberculosis Research Program, Centenary Institute)

  • Nicole A. deWeerd

    (Hudson Institute of Medical Research)

  • Sebastian A. Stifter

    (The University of Sydney
    Tuberculosis Research Program, Centenary Institute)

  • 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
    The University of Sydney)

  • Paul J. Hertzog

    (Hudson Institute of Medical Research)

  • Warwick J. Britton

    (Tuberculosis Research Program, Centenary Institute
    The University of Sydney)

  • Xinchun Chen

    (Guangdong Medical University
    Shenzhen University School of Medicine)

  • Carl G. Feng

    (Guangdong Medical University
    The University of Sydney
    Tuberculosis Research Program, Centenary Institute)

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.

Suggested Citation

  • 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. , 2018. "A proline deletion in IFNAR1 impairs IFN-signaling and underlies increased resistance to tuberculosis in humans," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02611-z
    DOI: 10.1038/s41467-017-02611-z
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