Single-cell profiling identifies ACE+ granuloma macrophages as a non-permissive 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 comprised of
macrophages and other immune cells. We apply single-cell transcriptomics
to investigate macrophage functional diversity during persistent
Salmonella 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 a STm 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+ macrophages have limited capacity to serve as cellular niche for
intracellular bacteria to establish persistent infection.