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

Mycobacterium tuberculosis (MTB) ESX-1, a type VII secretion system, is a
key virulence determinant contributing to MTB’s survival within lung
mononuclear phagocytes (MNPs), but its effect on MNP recruitment and
differentiation remains unknown. Here, using multiple single-cell RNA
sequencing techniques, we studied the role of ESX-1 in MNP heterogeneity
and response in mice and murine bone marrow-derived macrophages (BMDM). We
found that ESX-1 is required for MTB to recruit diverse MNP subsets with
high MTB burden. Further, MTB induces an anti-inflammatory transcriptional
signature in MNPs and BMDM in an ESX-1-dependent manner.  Spatial
transcriptomics revealed an upregulation of anti-inflammatory signals
within MTB lesions, where monocyte-derived macrophages concentrate near
MTB-infected cells. Together, our findings suggest that MTB ESX-1
facilitates the recruitment and differentiation of anti-inflammatory MNPs,
which MTB can infect and manipulate for survival. Importantly, we provide
a comprehensive transcriptomic dataset across various models and methods,
which could contribute to the broader understanding of recruited cell
heterogeneity during MTB lung infection.