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Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. An important question is how type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections. The Super susceptibility to tuberculosis 1 ( Sst1 ) locus in mice confers resistance to diverse bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that represses type I IFN transcription during bacterial infections. We generated Sp140 -/- mice and found that they are susceptible to infection by Legionella pneumophila and Mycobacterium tuberculosis . Susceptibility of Sp140 -/- mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor ( Ifnar -/- ). Our results implicate Sp140 as an important negative regulator of type I IFNs that is essential for resistance to bacterial infections., Competing Interests: DJ, KW, DK, SM, AL, VC, KC, MG, HD, AL, SN, DZ, IK, DP, KD No competing interests declared, RV consults for Ventus Therapeutics and is a Reviewing Editor for eLife, (© 2021, Ji et al.)

The bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis and is responsible for more human mortality than any other single pathogen 1 . Progression to active disease occurs in only a fraction of infected individuals and is predicted by an elevated type I interferon (IFN) response 2-7 . Whether or how IFNs mediate susceptibility to Mtb has been difficult to study due to a lack of suitable mouse models 6-11 . Here, we examined B6.Sst1 S congenic mice that carry the 'susceptible' allele of the Sst1 locus that results in exacerbated Mtb disease 12-14 . We found that enhanced production of type I IFNs was responsible for the susceptibility of B6.Sst1 S mice to Mtb. Type I IFNs affect the expression of hundreds of genes, several of which have previously been implicated in susceptibility to bacterial infections 6,7,15-18 . Nevertheless, we found that heterozygous deficiency in just a single IFN target gene, Il1rn, which encodes interleukin-1 receptor antagonist (IL-1Ra), is sufficient to reverse IFN-driven susceptibility to Mtb in B6.Sst1 S mice. In addition, antibody-mediated neutralization of IL-1Ra provided therapeutic benefit to Mtb-infected B6.Sst1 S mice. Our results illustrate the value of the B6.Sst1 S mouse to model IFN-driven susceptibility to Mtb, and demonstrate that IL-1Ra is an important mediator of type I IFN-driven susceptibility to Mtb infections in vivo.