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Title: Role of SPI-1 Secreted Effectors in Acute Bovine Response to Salmonella enterica Serovar Typhimurium: A Systems Biology Analysis Approach

Journal Article · · PLoS ONE
 [1];  [1];  [1];  [2];  [3];  [1];  [1];  [1];  [1];  [4];  [5];  [3];  [2];  [6];  [1]
  1. Texas A & M University, College Station, TX (United States)
  2. University of Illinois at Urbana-Champaign, IL (United States)
  3. University of Texas Southwestern Medical Center, Dallas, TX (United States)
  4. Sandia National Laboratory (SNL-NM), Albuquerque, NM (United States)
  5. Serologix, LLC, Austin, TX (United States)
  6. University of California, Davis, CA (United States)
+ Show Author Affiliations

Salmonella enterica Serovar Typhimurium (S. Typhimurium) causes enterocolitis with diarrhea and polymorphonuclear cell (PMN) influx into the intestinal mucosa in humans and calves. The Salmonella Type III Secretion System (T3SS) encoded at Pathogenicity Island I translocates Salmonella effector proteins SipA, SopA, SopB, SopD, and SopE2 into epithelial cells and is required for induction of diarrhea. These effector proteins act together to induce intestinal fluid secretion and transcription of C-X-C chemokines, recruiting PMNs to the infection site. While individual molecular interactions of the effectors with cultured host cells have been characterized, their combined role in intestinal fluid secretion and inflammation is less understood. We hypothesized that comparison of the bovine intestinal mucosal response to wild type Salmonella and a SipA, SopABDE2 effector mutant relative to uninfected bovine ileum would reveal heretofore unidentified diarrheaassociated host cellular pathways. To determine the coordinated effects of these virulence factors, a bovine ligated ileal loop model was used to measure responses to wild type S. Typhimurium (WT) and a ΔsipA, sopABDE2 mutant (MUT) across 12 hours of infection using a bovine microarray. Data were analyzed using standard microarray analysis and a dynamic Bayesian network modeling approach (DBN). Both analytical methods confirmed increased expression of immune response genes to Salmonella infection and novel gene expression. Gene expression changes mapped to 219 molecular interaction pathways and 1620 gene ontology groups. Bayesian network modeling identified effects of infection on several interrelated signaling pathways including MAPK, Phosphatidylinositol, mTOR, Calcium, Toll-like Receptor, CCR3, Wnt, TGF-β, and Regulation of Actin Cytoskeleton and Apoptosis that were used to model of host-pathogen interactions. Comparison of WT and MUT demonstrated significantly different patterns of host response at early time points of infection (15 minutes, 30 minutes and one hour) within phosphatidylinositol, CCR3, Wnt, and TGF-β signaling pathways and the regulation of actin cytoskeleton pathway.

Research Organization:
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institute of Allergy and Infectious Disease; Public Health Service Grant
Grant/Contract Number:
NA0003525; 1 R01 A144170-01-A1; 1 R01 AI076246 01-A2; USDA 2002-35204-12247; AI060933
OSTI ID:
1627481
Journal Information:
PLoS ONE, Vol. 6, Issue 11; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Reconstruction of the temporal signaling network in Salmonella-infected human cells journal July 2015
Global Rsh-dependent transcription profile of Brucella suisduring stringent response unravels adaptation to nutrient starvation and cross-talk with other stress responses journal July 2013
Animal models to study acute and chronic intestinal inflammation in mammals journal November 2015
Understanding the complexities of Salmonella-host crosstalk as revealed by in vivo model organisms: Model Systems of Salmonella-Host Crosstalk journal July 2015
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Systems Biology Analysis of Brucella Infected Peyer's Patch Reveals Rapid Invasion with Modest Transient Perturbations of the Host Transcriptome journal December 2013
Age-dependent enterocyte invasion and microcolony formation by Salmonella text January 2014
Beyond differential expression: the quest for causal mutations and effector molecules journal January 2012
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59 BASIC BIOLOGICAL SCIENCES
salmonella typhimurium
gene expression
salmonellosis
gastrointestinal tract
salmonella
microarrays
wnt signaling cascade
chemokines