Shared and distinct responses of human and murine alveolar macrophages and monocyte-derived macrophages to Mycobacterium tuberculosis

Macrophages serve as important sites of bacterial replication and host immune response during Mycobacterium tuberculosis (Mtb) infection with distinct roles for alveolar macrophages (AMs) early in infection and monocyte-derived (MDMs) during later stages of disease. Here, we leverage data from human and mouse models to perform a cross-species analysis of macrophage responses to Mtb infection. Overall, we find that both subsets of human and murine macrophages mount a strong interferon response to Mtb infection. However, AM across both species do not generate as strong a pro-inflammatory response as human MDMs or murine bone marrow-derived macrophages (BMDMs), as characterized by TNFA signaling and inflammatory response pathways. Interestingly, AMs from mice that were previously vaccinated with BCG (scBCG) or from a model of contained TB (coMtb) had Mtb responses that were more similar to human AMs than control mice. We also identify species-specific pathways altered by infection differently in mouse and human macrophages, specifically in pathways related to cholesterol in AMs as well as MYC targets and Hedgehog signaling in MDMs/BMDMs. Lastly, to investigate downstream effects of the macrophage interferon responses, we examine macrophage expression of IL-10, an immunosuppressive cytokine induced by Type I Interferons, and c-Maf, a transcription factor required for IL-10 expression in myeloid cells. We find that c-Maf and IL-10 have significantly lower expression in AMs compared to MDMs in both humans and mice, suggesting one possible mechanism by which AMs mount a stronger interferon response following Mtb infection. Overall, these results highlight the dynamics of innate myeloid responses over the course of Mtb infection and the benefit of a combined analysis across species to reveal conserved and unique responses.