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.
Highlights
Type I interferons (IFN), best known for their anti-viral functions, have been shown to impair host resistance to intracellular bacteria in mice
As an initial step in understanding the function of type I IFNs in human TB, we examined the expression of Interferon Stimulated Genes (ISG) in the leukocytes of healthy controls (HC), latent TB infection (LTBI) subjects and TB patients
In agreement with previous studies performed in African populations[19,20], we observed that PBMCs of active TB patients expressed significantly higher levels of ISGs than LTBI subjects in Chinese populations (Fig. 1a)
Summary
Type I interferons (IFN), best known for their anti-viral functions, have been shown to impair host resistance to intracellular bacteria in mice. 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. We further demonstrate that the SNP decreases type I IFN signaling by reducing the overall binding affinity of IFN-β for IFNAR1 These findings suggest a host-detrimental function for type I IFN signaling in human TB. As we show that the mutation, which occurs at a non-cytokine binding region of IFNAR1, weakens the cytokine receptor interaction, our findings suggest a function for the membrane-proximal domain in type I IFN binding and signaling
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