scRNA-seq Reveals A Macrophage Subset That Provides A Splenic Replication Niche For Intracellular Salmonella

Abstract

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-seq (scRNA-seq) have identified multiple subsets within the mononuclear population defined by unique molecular features, but the implications to their function during infection is unknown. Here, we applied high resolution kinetic analysis using microscopy, flow cytometry and scRNA-seq to survey the mononuclear niche of intracellular Salmonella Typhimurium (S.Tm) during early systemic infection in mice. We describe an 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 bacterial growth mediated by intracellular replication within a macrophage population we termed CD9 macrophages, that originate from non-classical monocytes. Nr4a1e2-/- mice, specifically depleted of non-classical monocytes but not other mononuclear cells, are more resistant to S.Tm infection. Our study underscores a cell-type specific host-pathogen interaction that determines early infection growth dynamics and has implications to the infection outcome of the entire organism.