Type I interferon-driven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra.

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.