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Single-cell analysis reveals Mycobacterium tuberculosis ESX-1–mediated accumulation of permissive macrophages in infected mouse lungs

ABSTRACT: 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/or 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE263891 | GEO | 2024/04/20

REPOSITORIES: GEO

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Single-cell analysis reveals Mycobacterium tuberculosis ESX-1–mediated accumulation of permissive macrophages in infected mouse lungs

Project description: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/or 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.

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