Fairgrieve, M. R. | Search bioRxiv

bioRxiv2026

Strong sustained type I IFN signaling acts cell intrinsically to impair IFNγ responses and cause tuberculosis susceptibility

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.

immunology↗

bioRxiv2025

Diverse infection models demonstrate robust resistance of Mycobacterium tuberculosis to innate immunity

Mycobacterium tuberculosis (Mtb) is a robust activator of innate immunity. However, there is little evidence that innate immune mechanisms control Mtb before the onset of adaptive immunity. Prior work has generally used specific pathogen-free (SPF) mouse models and relatively large infectious doses, which may obscure the capacity of innate immunity to control Mtb. Here, we performed ultra-low dose Mtb infections and found that the initial innate immune response was unable to curb even minimal Mtb infectious doses. Additionally, we primed the immune systems of C57BL/6 mice by co-housing with "pet shop" mice prior to Mtb exposure. Co-housed mice were as susceptible to Mtb infection as SPF mice. To pre-activate innate immunity at the site of Mtb infection more specifically, we also infected the lungs of mice with Legionella pneumophila (Lp) prior to Mtb. Innate immunity alone can clear large doses (>100,000 CFU) of Lp from the lung within a few days. However, priming the mouse lung by pre-infection with Lp only modestly reduced Mtb CFU compared to mice infected with only Mtb, indicating that Mtb can robustly replicate even in the presence of a strong anti-bacterial innate response. We performed single-cell RNA-sequencing on myeloid cells from mice either infected with Mtb alone or mice primed with Lp. We found that Lp priming before Mtb infection induced measurable changes in myeloid cells responding to Mtb, but these changes had little effect on innate control of Mtb. Together, these data demonstrate the robust resistance of Mtb to innate immune clearance under diverse experimental conditions.

immunology↗