Coordinated regulation of virulence during systemic infection of Salmonella enterica serovar Typhimurium

Hyunjin Yoon, Jason E. McDermott, Steffen Porwollik, Michael McClelland, Fred Heffron

    Research output: Contribution to journalArticle

    100 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish (US)
    Article numbere1000306
    JournalPLoS Pathogens
    Volume5
    Issue number2
    DOIs
    StatePublished - Feb 2009

    Fingerprint

    Salmonella enterica
    Virulence
    Salmonella
    Genomic Islands
    Virulence Factors
    Infection
    Genes
    Systems Biology
    Salmonella Infections
    Salmonella typhimurium
    Cues
    Cluster Analysis
    Serogroup

    ASJC Scopus subject areas

    • Microbiology
    • Parasitology
    • Virology
    • Immunology
    • Genetics
    • Molecular Biology

    Cite this

    Coordinated regulation of virulence during systemic infection of Salmonella enterica serovar Typhimurium. / Yoon, Hyunjin; McDermott, Jason E.; Porwollik, Steffen; McClelland, Michael; Heffron, Fred.

    In: PLoS Pathogens, Vol. 5, No. 2, e1000306, 02.2009.

    Research output: Contribution to journalArticle

    Yoon, Hyunjin ; McDermott, Jason E. ; Porwollik, Steffen ; McClelland, Michael ; Heffron, Fred. / Coordinated regulation of virulence during systemic infection of Salmonella enterica serovar Typhimurium. In: PLoS Pathogens. 2009 ; Vol. 5, No. 2.
    @article{704b8ba97b2e48ffbc12fffeae1958ec,
    title = "Coordinated regulation of virulence during systemic infection of Salmonella enterica serovar Typhimurium",
    abstract = "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.",
    author = "Hyunjin Yoon and McDermott, {Jason E.} and Steffen Porwollik and Michael McClelland and Fred Heffron",
    year = "2009",
    month = "2",
    doi = "10.1371/journal.ppat.1000306",
    language = "English (US)",
    volume = "5",
    journal = "PLoS Pathogens",
    issn = "1553-7366",
    publisher = "Public Library of Science",
    number = "2",

    }

    TY - JOUR

    T1 - Coordinated regulation of virulence during systemic infection of Salmonella enterica serovar Typhimurium

    AU - Yoon, Hyunjin

    AU - McDermott, Jason E.

    AU - Porwollik, Steffen

    AU - McClelland, Michael

    AU - Heffron, Fred

    PY - 2009/2

    Y1 - 2009/2

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=59649095559&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=59649095559&partnerID=8YFLogxK

    U2 - 10.1371/journal.ppat.1000306

    DO - 10.1371/journal.ppat.1000306

    M3 - Article

    C2 - 19229334

    AN - SCOPUS:59649095559

    VL - 5

    JO - PLoS Pathogens

    JF - PLoS Pathogens

    SN - 1553-7366

    IS - 2

    M1 - e1000306

    ER -