Single-cell analysis reveals M. tuberculosis ESX-1-mediated accumulation of anti-inflammatory macrophages in infected mouse lung

Mycobacterium tuberculosis (MTB) infects and replicates in lung mononuclear phagocytes (MNPs) with astounding ability to evade elimination. A virulence determinant that contributes to MTB's ability to survive within MNPs is ESX-1, a type VII secretion system. However, how MTB virulence factors influence mononuclear cell recruitment and differentiation remains unknown. Here, using single-cell RNA sequencing, we studied the role of ESX-1 in MNP heterogenicity and response in mice and murine bone marrow-derived macrophages. We found that ESX-1 is required for MTB to recruit diverse MNP subsets with high MTB burden. Further, MTB induces an anti-inflammatory signature that may lead to more permissive MNPs. Spatial transcriptomics revealed an upregulation of anti-inflammatory signals in MTB lesions, where monocyte derived macrophages concentrate near MTB infected cells. Together, our findings suggest that MTB ESX-1 mediates the recruitment and differentiation of anti-inflammatory MNPs, which MTB can infect and manipulate for survival.