Abstract
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a zoonotic pathogen that causes diarrheal disease in humans and animals. During salmonellosis, S. Typhimurium colonizes epithelial cells lining the gastrointestinal tract. S. Typhimurium has an unusual lifestyle in epithelial cells that begins within an endocytic-derived Salmonella-containing vacuole (SCV), followed by escape into the cytosol, epithelial cell lysis and bacterial release. The cytosol is a more permissive environment than the SCV and supports rapid bacterial growth. The physicochemical conditions encountered by S. Typhimurium within the epithelial cytosol, and the bacterial genes required for cytosolic colonization, remain largely unknown. Here we have exploited the parallel colonization strategies of S. Typhimurium in epithelial cells to decipher the two niche-specific bacterial virulence programs. By combining a population-based RNA-seq approach with single-cell microscopic analysis, we identified bacterial genes with cytosol-induced or vacuole-induced expression signatures. Using these genes as environmental biosensors, we defined that Salmonella is exposed to oxidative stress and iron and manganese deprivation in the cytosol and zinc and magnesium deprivation in the SCV. Furthermore, iron availability was critical for optimal S. Typhimurium replication in the cytosol, as well as entC, fepB, soxS, mntH and sitA. Virulence genes that are typically associated with extracellular bacteria, namely Salmonella pathogenicity island 1 (SPI1) and SPI4, showed increased expression in the cytosol compared to vacuole. Our study reveals that the cytosolic and vacuolar S. Typhimurium virulence gene programs are unique to, and tailored for, residence within distinct intracellular compartments. This archetypical vacuole-adapted pathogen therefore requires extensive transcriptional reprogramming to successfully colonize the mammalian cytosol.
Highlights
There are two major niches in which intracellular bacteria survive and proliferate after internalization into host cells, confined within a membrane-bound vacuole or free-living within the cytosol
We have exploited the parallel intracellular lifestyles of S. enterica in epithelial cells to identify the niche-specific bacterial expression profiles and environmental cues encountered by S. enterica
We have discovered bacterial genes that are required for colonization of the cytosol, but not the vacuole
Summary
There are two major niches in which intracellular bacteria survive and proliferate after internalization into host cells, confined within a membrane-bound vacuole or free-living within the cytosol. While bacterial pathogens have been historically categorized as being either vacuolar or cytosolic, it has recently been realized that some bacteria can occupy both niches, often in a celltype specific manner. Protozoal and viral diseases, non-typhoidal Salmonella enterica (NTS) cause the largest burden of illness and death worldwide [4]. T3SS2 is important for survival within phagocytic cells, which S. enterica encounters in the lamina propria during an enteric infection or in the mesenteric lymph nodes, reticuloendothelial tissues (liver and spleen) and circulating blood during invasive disease
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