Dissecting a novel stem-cell defense mechanism in early epithelial-specific responses to an enteric bacterial pathogen
2Department of Chemical Research Support, Weizmann Institute of Science, Israel
The gut is lined with a specialized monolayer epithelium composed of different intestinal epithelial cell types specialized in sensing and responding to environmental substances in close coordination with the underlying rich immune system. Salmonella enterica (S. enterica) represents one of the common pathogenic foodborne infections resulting in an acute inflammatory response in the gut. Although the physiopathology of Salmonella systemic infection has been investigated in depth in the past decades, the first steps of natural infection, occurring in the gut, by which S. enterica invades and affects the epithelial cells are still unknown. We dissected the epithelial cell-specific responses to S. enterica infection using single-cell RNA-seq and GFP-labeled pathogenic bacteria, coupled with a novel computational approach to identify an epithelial-specific signature of Salmonella cell-infected. We showed that infection by S. enterica results in epithelium composition skew within the first 24 hours, with depletion of intestinal stem cells (ISCs) and massive enterocyte differentiation. Furthermore, our data indicate two subtypes of intestinal epithelial cells prone to S. enterica infection: Paneth cells and enterocytes. These infected cells massively increase their production of antimicrobial proteins, which help to eradicate this pathogen from the lumen. Surprisingly, close inspection of ISCs, residing next to Paneth cells, revealed a novel stem-cell protective mechanism against S. enterica infection. We identified that infected stem cells undergo programmed differentiation toward Paneth cells and enterocytes to eliminate infected stem cells from the stem-cell pool. Overall, we identified a novel epithelial-specific S. enterica infection signature and specific-epithelial cell response to this infectious pathogen.