title: Complex c-di-GMP signaling networks mediate transition between virulence properties and biofilm formation in Salmonella enterica serovar Typhimurium.
abstract: Upon Salmonella enterica serovar Typhimurium infection of the gut, an early line of defense is the gastrointestinal epithelium which senses the pathogen and intrusion along the epithelial barrier is one of the first events towards disease. Recently, we showed that high intracellular amounts of the secondary messenger c-di-GMP in S. typhimurium inhibited invasion and abolished induction of a pro-inflammatory immune response in the colonic epithelial cell line HT-29 suggesting regulation of transition between biofilm formation and virulence by c-di-GMP in the intestine. Here we show that highly complex c-di-GMP signaling networks consisting of distinct groups of c-di-GMP synthesizing and degrading proteins modulate the virulence phenotypes invasion, IL-8 production and in vivo colonization in the streptomycin-treated mouse model implying a spatial and timely modulation of virulence properties in S. typhimurium by c-di-GMP signaling. Inhibition of the invasion and IL-8 induction phenotype by c-di-GMP (partially) requires the major biofilm activator CsgD and/or BcsA, the synthase for the extracellular matrix component cellulose. Inhibition of the invasion phenotype is associated with inhibition of secretion of the type three secretion system effector protein SipA, which requires c-di-GMP metabolizing proteins, but not their catalytic activity. Our findings show that c-di-GMP signaling is at least equally important in the regulation of Salmonella-host interaction as in the regulation of biofilm formation at ambient temperature.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Irfan
authors.initials: I
authors.lastname: Ahmad
authors.forename: Agaristi
authors.initials: A
authors.lastname: Lamprokostopoulou
authors.forename: Soazig
authors.initials: S
authors.lastname: Le Guyon
authors.forename: Elena
authors.initials: E
authors.lastname: Streck
authors.forename: Melanie
authors.initials: M
authors.lastname: Barthel
authors.forename: Verena
authors.initials: V
authors.lastname: Peters
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Hardt
authors.forename: Ute
authors.initials: U
authors.lastname: Römling
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D018441:Biofilms; D002450:Cell Communication; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D004847:Epithelial Cells / Q000382:microbiology; D015964:Gene Expression Regulation, Bacterial; D019073:HT29 Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007422:Intestines / Q000382:microbiology; D008840:Microfilament Proteins / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D019779:Salmonella enterica / Q000378:metabolism*; D015398:Signal Transduction; D013696:Temperature; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D016209:Interleukin-8; D008840:Microfilament Proteins; C118287:SipA protein, Salmonella; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP