A non-classical monocyte-derived macrophage subset provides a splenic replication niche for intracellular Salmonella

Abstract

Summary Interactions between intracellular bacteria and mononuclear phagocytes give rise to diverse cellular phenotypes that may determine the outcome of infection. Recent advances in single-cell RNA sequencing (scRNA-seq) have identified multiple subsets within the mononuclear population, but implications to their function during infection are limited. Here, we surveyed the mononuclear niche of intracellular Salmonella Typhimurium ( S .Tm) during early systemic infection in mice. We described eclipse-like growth kinetics in the spleen, with a first phase of bacterial control mediated by tissue-resident red-pulp macrophages. A second phase involved extensive bacterial replication within a macrophage population characterized by CD9 expression. We demonstrated that CD9 + macrophages induced pathways for detoxificating oxidized lipids, that may be utilized by intracellular S .Tm. We established that CD9 + macrophages originated from non-classical monocytes (NCM), and NCM-depleted mice were more resistant to S .Tm infection. Our study defines macrophage subset-specific host-pathogen interactions that determine early infection dynamics and infection outcome of the entire organism.

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

“…Yet these crucial immune cells can also act as a cellular niche and form granulomas, which are immunological structures that function as a host mechanism to contain infection but within which intracellular bacteria are able to survive. Understanding of macrophage functional diversity requires delineation not only of macrophages within granulomas but also precursor cells that give rise to these and other macrophages in the infected tissue environment (32,35,37,57).…”

“…Yet these crucial immune cells can also act as a cellular niche and form granulomas, which are immunological structures that function as a host mechanism to contain infection but within which intracellular bacteria are able to survive. Understanding of macrophage functional diversity requires delineation not only of macrophages within granulomas but also precursor cells that give rise to these and other macrophages in the infected tissue environment(32, 35, 37, 57). Here, we apply single-cell transcriptomics to investigate macrophage heterogeneity in S Tm-infected spleens to gain insight into how their heterogeneity and functional diversity contribute to controlling bacterial persistence and infection.…”

“…Despite their ability to restrict intracellular bacilli, alveolar macrophages were shown to exhibit M2-like characteristics and thereby served as a more favorable replicative niche for Mtb (27, 36). In a recent single-cell RNA-sequencing (sc-RNAseq) study of acute S Tm infection in mice for 48 hours after inoculation, when granulomas are yet to form and bacterial levels are uncontrolled, a non-classical monocyte-derived macrophage population was found to harbor more intracellular bacilli than other mononuclear phagocytes(37).…”

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

“…Despite their ability to restrict intracellular bacilli, alveolar MΦs were shown to exhibit M2-like characteristics and thereby served as a more favorable replicative niche for Mtb . In a recent single-cell RNA sequencing (scRNA-seq) study of acute S Tm infection in mice for 48 hours after inoculation, when granulomas are yet to form and bacterial levels are uncontrolled, a non–classical monocyte (CM)–derived MΦ population was found to harbor more intracellular bacilli than other mononuclear phagocytes (MNPs) ( 27 ).…”

Paired single-cell host profiling with multiplex-tagged bacterial mutants reveals intracellular virulence-immune networks

“…On the host side, macrophages infected with S .Tm generates well-documented heterogeneous phenotypes during intracellular infection (Burton et al, 2014). Recent single cell RNA-seq (scRNA-seq) studies revealed host signatures of macrophage subpopulations that display diverse outcomes: some are permissive to intracellular bacterial growth (Hoffman et al, 2021); some will lyse the ingested bacteria (Huang et al, 2018); others allow bacteria to persist intracellularly (Stapels et al, 2018). But scRNA-seq methods are limited to profiling only host transcripts as they rely on polyA priming of mRNAs, while bacterial mRNAs lack polyA.…”