Single-cell Analysis Reveals ESX-1-mediated Accumulation of Permissive Macrophages in Infected Mouse Lungs

Overview

Journal Sci Adv

Date 2025 Jan 15

PMID 39813329

Authors

Weihao Zheng

Michael Borja

Leah C Dorman

Jonathan Liu

Andy Zhou

Amanda Seng

Ritwicq Arjyal

Sara Sunshine

Alina Nalyvayko

Angela Oliveira Pisco

Oren S Rosenberg

Norma Neff

Beth Shoshana Zha

Affiliations

Soon will be listed here.

Abstract

(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 a transcriptional signature of immune evasion in lung macrophages and BMDM in an ESX-1-dependent manner. Spatial transcriptomics revealed an up-regulation of permissive features 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 MNPs, which MTB can infect and manipulate for survival. Our dataset across various models and methods could contribute to the broader understanding of recruited cell heterogeneity during MTB lung infection.

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