@article {Ji389288, author = {Daisy X. Ji and Katherine J. Chen and Naofumi Mukaida and Igor Kramnik and K. Heran Darwin and Russell E. Vance}, title = {Interleukin-1 receptor antagonist mediates type I interferon-driven susceptibility to Mycobacterium tuberculosis}, elocation-id = {389288}, year = {2018}, doi = {10.1101/389288}, publisher = {Cold Spring Harbor Laboratory}, abstract = {The bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) and is responsible for more human mortality than any other single pathogen1. Although ~1.7 billion people are infected with Mtb2, most infections are asymptomatic. Progression to active disease occurs in ~10\% of infected individuals and is predicted by an elevated type I interferon (IFN) response3{\textendash}8. Type I IFNs are vital for antiviral immunity, but whether or how they mediate susceptibility to Mtb has been difficult to study, in part because the standard C57BL/6 (B6) mouse model does not recapitulate the IFN-driven disease that appears to occur in humans3{\textendash}5,8. Here we examined B6. Sst1S congenic mice that carry the C3H {\textquotedblleft}sensitive{\textquotedblright} allele of the Sst1 locus that renders them highly susceptible to Mtb infections9,10. We found that B6.Sst1S mice exhibit markedly increased type I IFN signaling, and that type I IFNs were required for the enhanced susceptibility of B6. Sst1S mice to Mtb. Type I IFNs affect the expression of hundreds of genes, several of which have previously been implicated in susceptibility to bacterial infections11,12. Nevertheless, we found that heterozygous deficiency in just a single IFN target gene, IL-1 receptor antagonist (IL-1Ra), is sufficient to reverse IFN-driven susceptibility to Mtb. As even a partial reduction in IL-1Ra levels led to significant protection, we hypothesized that IL-1Ra may be a plausible target for host-directed anti-TB therapy. Indeed, antibody-mediated neutralization of IL-1Ra provided therapeutic benefit to Mtb-infected B6. Sst1S mice. Our results illustrate how the diversity of inbred mouse strains can be exploited to better model human TB, and demonstrate that IL-1Ra is an important mediator of type I IFN-driven susceptibility to Mtb infections in vivo.}, URL = {https://www.biorxiv.org/content/early/2018/08/10/389288}, eprint = {https://www.biorxiv.org/content/early/2018/08/10/389288.full.pdf}, journal = {bioRxiv} }