Immunosuppression is a conserved driver of tuberculosis susceptibility

Abstract

SummaryMycobacterium tuberculosis(Mtb) causes 1.6 million deaths a year1. However, no individual mouse model fully recapitulates the hallmarks of human tuberculosis disease. Here we report that a comparison across three different susceptible mouse models identifiesMtb-induced gene signatures that predict active TB disease in humans significantly better than a signature from the standard C57BL/6 mouse model. An increase in lung myeloid cells, including neutrophils, was conserved across the susceptible mouse models, mimicking the neutrophilic inflammation observed in humans2,3. Myeloid cells in the susceptible models and non-human primates exhibited high expression of immunosuppressive molecules including the IL-1 receptor antagonist, which inhibits IL-1 signaling. Prior reports have suggested that excessive IL-1 signaling impairsMtbcontrol4–6. By contrast, we found that enhancement of IL-1 signaling via deletion of IL-1 receptor antagonist promoted bacterial control in all three susceptible mouse models. IL-1 signaling enhanced cytokine production by lymphoid and stromal cells, suggesting a mechanism for IL-1 signaling in promotingMtbcontrol. Thus, we propose that myeloid cell expression of immunosuppressive molecules is a conserved mechanism exacerbatingMtbdisease in mice, non-human primates, and humans.