Single-cell profiling identifies ACE+granuloma macrophages as a non-permissive niche for intracellular bacteria during persistentSalmonellainfection

Macrophages mediate key antimicrobial responses against intracellular bacterial pathogens, such as Salmonella enterica . Yet, they can also act as a permissive niche for these pathogens to persist in infected tissues within granulomas, which are immunological structures comprised of macrophages and other immune cells. We apply single-cell transcriptomics to investigate macrophage functional diversity during persistent Salmonella enterica serovar Typhimurium ( S Tm) infection in mice. We identify determinants of macrophage heterogeneity in infected spleens and describe populations of distinct phenotypes, functional programming, and spatial localization. Using a S Tm mutant with impaired ability to polarize macrophage phenotypes, we find that angiotensin converting enzyme (ACE) defines a granuloma macrophage population that is non-permissive for intracellular bacteria and their abundance anticorrelates with tissue bacterial burden. Disruption of pathogen control by neutralizing TNF preferentially depletes ACE + macrophages in infected tissues. Thus ACE + macrophages have differential capacity to serve as cellular niche for intracellular bacteria to establish persistent infection. Teaser This study shows that ACE + granuloma macrophages have restricted capacity to act as a cellular niche that enables intracellular bacterial persistence.