Strong sustained type I IFN signaling acts cell intrinsically to impair IFNγ responses and cause tuberculosis susceptibility
Fattinger, S. A.; Chavez, R. A.; Witt, K. C.; Parisi, B.; Rodriguez, J. J.; Turcotte, E. A.; Brydon, E. C.; Fairgrieve, M. R.; Dhaliwal, H.; Lee, A. Y.; Kotov, D. I.; Vance, R. E.
Show abstract
Mycobacterium tuberculosis (Mtb) causes over one million annual deaths, but most infected individuals never exhibit symptoms. Type I interferons (IFNs) have emerged as a major factor driving Mtb susceptibility, but how type I IFNs impair immunity to Mtb is a key unresolved question. Here we show that an early and primary effect of type I IFN during Mtb infection is the cell-intrinsic impairment of IFN{gamma} signaling. IFN{gamma} signaling was selectively impaired in the subset of infected macrophages experiencing high and sustained levels of type I IFN signaling. Genetic elimination of RESIST, a recently described positive regulator of type I IFN production, specifically eliminated the high and sustained type I IFN response, fully restored IFN{gamma} signaling, and rescued Mtb susceptibility without affecting basal type I IFN responses. Our results demonstrate that strong and sustained type I IFN responses specifically and cell-intrinsically impair responsiveness to IFN{gamma} to cause Mtb susceptibility.
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