Interleukin-1 receptor antagonist is a conserved driver of tuberculosis

Mycobacterium tuberculosis (Mtb) causes 1.3 million deaths a year. However, tuberculosis (TB) pathogenesis remains poorly understood and is not fully recapitulated in standard mouse models. Here we find that gene signatures from three different Mtb-susceptible mouse models predict active TB disease in humans significantly better than a signature from resistant C57BL/6 (B6) mice. Conserved among susceptible mice and non-human primates, but largely absent from B6 mice, was Mtb-induced differentiation of macrophages into an alternatively activated Spp1+ differentiation state. Spp1+ macrophages expressed high levels of immunosuppressive molecules including IL-1 receptor antagonist (IL-1Ra). IL-1Ra was previously reported to cause Mtb susceptibility in one mouse model, but whether IL-1Ra is broadly important remains uncertain. Indeed, in other models, Mtb-susceptibility is proposed to result from excessive rather than diminished IL-1 signaling. Here we report that enhancement of IL-1 signaling via deletion of IL-Ra promoted bacterial control across three susceptible mouse models. We found IL-1 signaling enhanced production of multiple cytokines by lymphoid and stromal cells, providing a multifactorial mechanism for how IL-1 promotes Mtb control. Our results indicate that myeloid cell expression of immunosuppressive molecules, in particular IL-1 receptor antagonist, is a conserved mechanism exacerbating Mtb disease in mice, non-human primates, and humans. ### Competing Interest Statement R.E.V. consults for Tempest Therapeutics and X-biotix Therapeutics.