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

<p>Macrophages mediate key antimicrobial responses against intracellular bacterial pathogens, such as <em>Salmonella enterica</em>. 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 <em>Salmonella</em> <em>enterica</em> serovar Typhimurium (<em>S</em>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 <em>S</em>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 is linked to preferential depletion of ACE⁺ macrophages in infected tissues. Thus ACE<em>⁺</em> macrophages have limited capacity to serve as cellular niche for intracellular bacteria to establish persistent infection.</p>