title: Role of SPI-1 secreted effectors in acute bovine response to Salmonella enterica Serovar Typhimurium: a systems biology analysis approach.
abstract: 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 diarrhea-associated 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.
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A &M University, College Station, Texas, United States of America.
authors.forename: Sara D
authors.initials: SD
authors.lastname: Lawhon
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Khare
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rossetti
authors.forename: Robin E
authors.initials: RE
authors.lastname: Everts
authors.forename: Cristi L
authors.initials: CL
authors.lastname: Galindo
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Luciano
authors.forename: Josely F
authors.initials: JF
authors.lastname: Figueiredo
authors.forename: Jairo E S
authors.initials: JE
authors.lastname: Nunes
authors.forename: Tamara
authors.initials: T
authors.lastname: Gull
authors.forename: George S
authors.initials: GS
authors.lastname: Davidson
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Drake
authors.forename: Harold R
authors.initials: HR
authors.lastname: Garner
authors.forename: Harris A
authors.initials: HA
authors.lastname: Lewin
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Bäumler
authors.forename: Leslie Garry
authors.initials: LG
authors.lastname: Adams
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D001499:Bayes Theorem; D002417:Cattle; D018932:Chemokine CCL2 / Q000378:metabolism; D054412:Chemokine CCL8 / Q000378:metabolism; D054427:Chemokine CXCL6 / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology*; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D010581:Peyer's Patches / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000378:metabolism; D012486:Salmonella typhimurium / Q000276:immunology* / Q000378:metabolism* / Q000472:pathogenicity; D015398:Signal Transduction / Q000502:physiology; D049490:Systems Biology / Q000379:methods*
chemical_list: D001426:Bacterial Proteins; D018932:Chemokine CCL2; D054412:Chemokine CCL8; D054427:Chemokine CXCL6; D020662:Guanine Nucleotide Exchange Factors; D016209:Interleukin-8; D008840:Microfilament Proteins; C118287:SipA protein, Salmonella; C116105:SopD protein, Salmonella; C436324:SopE2 protein, Salmonella typhimurium; C060971:SopA protein, Bacteria; C489224:SopB protein, Salmonella
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