The bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) 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 "sensitive" allele of the Sst1 locus that confers susceptibility to Mtb 12-14. We found that enhanced production of type I IFNs was responsible for the susceptibility of B6.

The Stimulator of Interferon Genes (STING) pathway initiates potent immune responses upon recognition of DNA. To initiate signaling, serine 365 (S365) in the C-terminal tail (CTT) of STING is phosphorylated, leading to induction of type I interferons (IFNs). Additionally, evolutionary conserved responses such as autophagy also occur downstream of STING, but their relative importance during in vivo infections remains unclear. Here we report that mice harboring a serine 365-to-alanine (S365A) mutation in STING are unexpectedly resistant to Herpes Simplex Virus (HSV)-1, despite lacking STING-induced type I IFN responses. By contrast, resistance to HSV-1 is abolished in mice lacking the STING CTT, suggesting that the STING CTT initiates protective responses against HSV-1, independently of type I IFNs. Interestingly, we find that STING-induced autophagy is a CTT-and TBK1-dependent but IRF3independent process that is conserved in the STING S365A mice. Thus, interferonindependent functions of STING mediate STING-dependent antiviral responses in vivo.

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 find 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.

Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. How type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections, remains poorly understood. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to many bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that functions to repress the expression of type I IFNs during bacterial infections. We generated Sp140 -/mice and find they are susceptible to infection by diverse bacteria, including Listeria monocytogenes, 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 repressor of type I IFNs that is essential for resistance to bacterial infections.