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.

doi:10.64898/2026.01.19.700487

bioRxiv · 10.64898/2026.01.19.700487

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.

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Abstract

Mycobacterium tuberculosis (Mtb) causes over one million deaths annually, but most infected individuals never exhibit symptoms. Type I interferons (IFNs) have emerged as a major factor driving susceptibility to Mtb, but how type I IFNs impair immunity to Mtb is a key unresolved question. Here we show that an early 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 susceptibility to Mtb 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 susceptibility to Mtb.

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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.. 2026-01-22. Strong sustained type I IFN signaling acts cell intrinsically to impair IFNγ responses and cause tuberculosis susceptibility. https://doi.org/10.64898/2026.01.19.700487

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