Coordinated Regulation of Virulence during Systemic Infection of Salmonella enterica serovar Typhimurium

Journal Article · Fri Feb 20 04:00:00 EST 2009 · PLoS Pathogens, 5(2):1-16

DOI:https://doi.org/10.1371/journal.ppat.1000306· OSTI ID:950178

Yoon, Hyunjin; McDermott, Jason E; Porwollik, Steffen; Mcclelland, Michael; Heffron, Fred

Salmonella must respond to a myriad of environmental cues during infection of a mouse and express specific subsets of genes in a temporal and spatial manner to subvert the host defense mechanisms but these 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 84 regulators inferred to play a role in Salmonella typhimurium virulence and tested them in three virulence assays (intraperitoneal (i.p.), and intragastric (i.g.) infection in BALB/c mice, and persistence in SvJ129 mice). Overall 36 regulators were identified that were less virulent in at least one assay, and of those, 15 regulators were required for systemic mouse infection in an acute infection model. As a first step towards understanding the interplay between a pathogen and its host from a systems biology standpoint we focused on these 15 genes. Transcriptional profiles were obtained for each of these 15 regulators from strains 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 15 regulators control a specific 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, for these 7 genes, the response regulator SsrB and the marR type regulator SlyA co-regulate in a regulatory cascade by integrating multiple signals.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (US)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 950178
• Report Number(s): PNNL-SA-61974
• Journal Information: PLoS Pathogens, 5(2):1-16, Journal Name: PLoS Pathogens, 5(2):1-16 Journal Issue: 2 Vol. 5
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ALGORITHMS
BIOLOGY
GENES
MICE
MONITORING
PATHOGENS
REGULATIONS
SALMONELLA
SALMONELLA TYPHIMURIUM
STRAINS
Salmonella
Salmonella pathogenicity island (SPI)
TRANSCRIPTION
VIRULENCE
mus musculus
regulators
systemic infection
transcriptional profiling
virulence