Immunosuppression is a conserved driver of tuberculosis susceptibility

Abstract

Mycobacterium tuberculosis (Mtb) causes 1.25 million deaths a year; however, tuberculosis (TB) pathogenesis remains poorly understood. 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, non-human primates, and humans, but largely absent from B6 mice, was Mtb-induced Spp1+ macrophage differentiation. Spp1+ macrophages expressed high levels of immunosuppressive molecules including IL-1 receptor antagonist (IL-1Ra). Here we report that enhancement of IL-1 signaling via deletion of IL-1Ra promoted bacterial control across three susceptible mouse models. We found that IL-1 signaling promotes pulmonary control of Mtb infection through amplifying TNF production by uninfected bystander cells. Our results indicate that myeloid cell expression of immunosuppressive molecules, in particular IL-1 receptor antagonist, is a conserved mechanism limiting Mtb control in mice, non-human primates, and humans.