title: Bile Acids Function Synergistically To Repress Invasion Gene Expression in Salmonella by Destabilizing the Invasion Regulator HilD.
abstract: Salmonella spp. are carried by and can acutely infect agricultural animals and humans. After ingestion, salmonellae traverse the upper digestive tract and initiate tissue invasion of the distal ileum, a virulence process carried out by the type III secretion system encoded within Salmonella pathogenicity island 1 (SPI-1). Salmonellae coordinate SPI-1 expression with anatomical location via environmental cues, one of which is bile, a complex digestive fluid that causes potent repression of SPI-1 genes. The individual components of bile responsible for SPI-1 repression have not been previously characterized, nor have the bacterial signaling processes that modulate their effects been determined. Here, we characterize the mechanism by which bile represses SPI-1 expression. Individual bile acids exhibit repressive activity on SPI-1-regulated genes that requires neither passive diffusion nor OmpF-mediated entry. By using genetic methods, the effects of bile and bile acids were shown to require the invasion gene transcriptional activator hilD and to function independently of known upstream signaling pathways. Protein analysis techniques showed that SPI-1 repression by bile acids is mediated by posttranslational destabilization of HilD. Finally, we found that bile acids function synergistically to achieve the overall repressive activity of bile. These studies demonstrate a common mechanism by which diverse environmental cues (e.g., certain short-chain fatty acids and bile acids) inhibit SPI-1 expression. These data provide information relevant to Salmonella pathogenesis during acute infection in the intestine and during chronic infection of the gallbladder and inform the basis for development of therapeutics to inhibit invasion as a means of repressing Salmonella pathogenicity.
authors.affiliation: Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA cre43@cornell.edu.
authors.forename: Colleen R
authors.identifier: http://orcid.org/0000-0002-1009-0420
authors.initials: CR
authors.lastname: Eade
authors.affiliation: Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
authors.forename: Chien-Che
authors.identifier: http://orcid.org/0000-0002-0338-6776
authors.initials: CC
authors.lastname: Hung
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Bullard
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Gonzalez-Escobedo
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Gunn
authors.affiliation: Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Altier
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D001647:Bile Acids and Salts / Q000494:pharmacology*; D020355:Cholates / Q000494:pharmacology; D004357:Drug Synergism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D018272:Porins / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D012475:Salmonella / Q000187:drug effects* / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D001647:Bile Acids and Salts; D020355:Cholates; C119660:HilD protein, Salmonella typhimurium; C113724:OmpC protein; C109237:OmpF protein; D018272:Porins; D014157:Transcription Factors