Single-cell profiling identifies ACE plus granuloma macrophages as a nonpermissive niche for intracellular bacteria during persistent Salmonella infection

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 composed of macrophages and other immune cells. We apply single-cell transcriptomics to investigate macrophage functional diversity during persistent S. enterica serovar Typhimurium (STm) infection in mice. We identify determinants of macrophage heterogeneity in infected spleens and describe populations of distinct phenotypes, functional programming, and spatial localization. Using an STm mutant with impaired ability to polarize macrophage phenotypes, we find that angiotensin-con-verting enzyme (ACE) defines a granuloma macrophage population that is nonpermissive for intracellular bac-teria, and their abundance anticorrelates with tissue bacterial burden. Disruption of pathogen control by neutralizing TNF is linked to preferential depletion of ACE+ macrophages in infected tissues. Thus, ACE+ macro-phages have limited capacity to serve as cellular niche for intracellular bacteria to establish persistent infection.

Automated summary

Macrophages play both a crucial role in antimicrobial responses against intracellular bacterial pathogens and a permissive role in allowing these pathogens to persist in infected tissues. Through single-cell transcriptomics, we identify determinants of macrophage heterogeneity during persistent infection and describe distinct populations with different functions and spatial localization. We find that angiotensin-converting enzyme (ACE) defines a macrophage population in granulomas that is nonpermissive for intracellular bacteria, and disruption of pathogen control is linked to preferential depletion of ACE+ macrophages.