Host succinate is a signal for activation of Salmonella virulence during intracellular infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Salmonella enterica subsp. enterica serovar Typhimurium
PROVIDER: GSE139208 | GEO | 2022/10/19
REPOSITORIES: GEO
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Project description:Intracellular pathogens, such as Salmonella enterica serovar Typhimurium (S.Tm), are able to sense and respond to a changing host cell environment. Macrophages exposed to microbial products undergo metabolic changes that are increasingly understood to drive a productive inflammatory response. However, the role of macrophage metabolic reprogramming in bacterial adaptation to the intracellular environment has not been explored. Here we show that changes in host metabolic state serve as a signal detected byS.Tm. Using metabolic profiling and dual RNA-seq, we show that succinate accumulates in infected macrophages and is sensed by intracellular S.Tm to promote induction of virulence genes. Succinate uptake by the bacterium drives induction of pmrAB-dependent genes and SPI-2 virulence-associated regulon. S.Tm lacking the DcuB transporter for succinate uptake display impaired intracellular survival. Our work demonstrates that accumulation of metabolic intermediates, necessary for macrophage activation, promote intracellular survival of pathogens, opening a new realm of metabolic host-pathogen crosstalk.
2022-10-19 | GSE139207 | GEO
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Project description:To cause a systemic infection, Salmonella must respond to many environmental cues during mouse infection and express specific subsets of genes in a temporal and spatial manner, but the regulatory pathways are poorly established. To unravel how micro-environmental signals are processed and integrated into coordinated action, we constructed in-frame non-polar deletions of 83 regulators inferred to play a role in Salmonella enteriditis Typhimurium (STM) virulence and tested them in three virulence assays (intraperitoneal [i.p.], and intragastric [i.g.] infection in BALB/c mice, and persistence in 129X1/SvJ mice). Overall, 35 regulators were identified whose absence attenuated virulence in at least one assay, and of those, 14 regulators were required for systemic mouse infection, the most stringent virulence assay. As a first step towards understanding the interplay between a pathogen and its host from a systems biology standpoint, we focused on these 14 genes. Transcriptional profiles were obtained for deletions of each of these 14 regulators grown under four different environmental conditions. These results, as well as publicly available transcriptional profiles, were analyzed using both network inference and cluster analysis algorithms. The analysis predicts a regulatory network in which all 14 regulators control the same set of genes necessary for Salmonella to cause systemic infection. We tested the regulatory model by expressing a subset of the regulators in trans and monitoring transcription of 7 known virulence factors located within Salmonella pathogenicity island 2 (SPI-2). These experiments validated the regulatory model and showed that the response regulator SsrB and the MarR type regulator, SlyA, are the terminal regulators in a cascade that integrates multiple signals. Furthermore, experiments to demonstrate epistatic relationships showed that SsrB can replace SlyA and, in some cases, SlyA can replace SsrB for expression of SPI-2 encoded virulence factors.
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