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RNA chaperone activates Salmonella virulence program during infection.

ABSTRACT: Organisms often harbor seemingly redundant proteins. In the bacterium Salmonella enterica serovar Typhimurium (S. Typhimurium), the RNA chaperones CspC and CspE appear to play redundant virulence roles because a mutant lacking both chaperones is attenuated, whereas mutants lacking only one exhibit wild-type virulence. We now report that CspC-but not CspE-is necessary to activate the master virulence regulator PhoP when S. Typhimurium experiences mildly acidic pH, such as inside macrophages. This CspC-dependent PhoP activation is specific to mildly acidic pH because a cspC mutant behaves like wild-type S. Typhimurium under other PhoP-activating conditions. Moreover, it is mediated by ugtL, a virulence gene required for PhoP activation inside macrophages. Purified CspC promotes ugtL translation by disrupting a secondary structure in the ugtL mRNA that occludes ugtL's ribosome binding site. Our findings demonstrate that proteins that are seemingly redundant actually confer distinct and critical functions to the lifestyle of an organism.

SUBMITTER: Choi J

PROVIDER: S-EPMC8599858 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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RNA chaperone activates Salmonella virulence program during infection.

Choi Jeongjoon J Salvail Hubert H Groisman Eduardo A EA

Nucleic acids research 20211101 20

Organisms often harbor seemingly redundant proteins. In the bacterium Salmonella enterica serovar Typhimurium (S. Typhimurium), the RNA chaperones CspC and CspE appear to play redundant virulence roles because a mutant lacking both chaperones is attenuated, whereas mutants lacking only one exhibit wild-type virulence. We now report that CspC-but not CspE-is necessary to activate the master virulence regulator PhoP when S. Typhimurium experiences mildly acidic pH, such as inside macrophages. This ...[more]

PMID: 34751407

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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.

Project description:UnlabelledTo establish a replicative niche during its infectious cycle between the intestinal lumen and tissue, the enteric pathogen Salmonella enterica serovar Typhimurium requires numerous virulence genes, including genes for two type III secretion systems (T3SS) and their cognate effectors. To better understand the host-pathogen relationship, including early infection dynamics and induction kinetics of the bacterial virulence program in the context of a natural host, we monitored the subcellular localization and temporal expression of T3SS-1 and T3SS-2 using fluorescent single-cell reporters in a bovine, ligated ileal loop model of infection. We observed that the majority of bacteria at 2 h postinfection are flagellated, express T3SS-1 but not T3SS-2, and are associated with the epithelium or with extruding enterocytes. In epithelial cells, S. Typhimurium cells were surrounded by intact vacuolar membranes or present within membrane-compromised vacuoles that typically contained numerous vesicular structures. By 8 h postinfection, T3SS-2-expressing bacteria were detected in the lamina propria and in the underlying mucosa, while T3SS-1-expressing bacteria were in the lumen. Our work identifies for the first time the temporal and spatial regulation of T3SS-1 and -2 expression during an enteric infection in a natural host and provides further support for the concept of cytosolic S. Typhimurium in extruding epithelium as a mechanism for reseeding the lumen.ImportanceThe pathogenic bacterium Salmonella enterica serovar Typhimurium invades and persists within host cells using distinct sets of virulence genes. Genes from Salmonella pathogenicity island 1 (SPI-1) are used to initiate contact and facilitate uptake into nonphagocytic host cells, while genes within SPI-2 allow the pathogen to colonize host cells. While many studies have identified bacterial virulence determinants in animal models of infection, very few have focused on virulence gene expression at the single-cell level during an in vivo infection. To better understand when and where bacterial virulence factors are expressed during an acute enteric infection of a natural host, we infected bovine jejunal-ileal loops with S. Typhimurium cells harboring fluorescent transcriptional reporters for SPI-1 and -2 (PinvF and PssaG, respectively). After a prescribed time of infection, tissue and luminal fluid were collected and analyzed by microscopy. During early infection (?2 h), bacteria within both intact and compromised membrane-bound vacuoles were observed within the epithelium, with the majority expressing SPI-1. As the infection progressed, S. Typhimurium displayed differential expression of the SPI-1 and SPI-2 regulons, with the majority of tissue-associated bacteria expressing SPI-2 and the majority of lumen-associated bacteria expressing SPI-1. This underscores the finding that Salmonella virulence gene expression changes as the pathogen transitions from one anatomical location to the next.

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RNA chaperone activates Salmonella virulence program during infection.

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RNA chaperone activates Salmonella virulence program during infection.

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