A diffusible signal factor of the intestine dictates Salmonella invasion through its direct control of the virulence activator HilD

Rimi Chowdhury; Paulina D Pavinski Bitar; Ivan Keresztes; Anthony M Condo Jr; Craig Altier

doi:10.1371/journal.ppat.1009357

A diffusible signal factor of the intestine dictates Salmonella invasion through its direct control of the virulence activator HilD

PLoS Pathog. 2021 Feb 22;17(2):e1009357. doi: 10.1371/journal.ppat.1009357. eCollection 2021 Feb.

Authors

Rimi Chowdhury¹, Paulina D Pavinski Bitar¹, Ivan Keresztes², Anthony M Condo Jr², Craig Altier¹

Affiliations

¹ Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
² Chemistry NMR Facility, Cornell University, Ithaca, New York, United States of America.

Abstract

Successful intestinal infection by Salmonella requires optimized invasion of the gut epithelium, a function that is energetically costly. Salmonella have therefore evolved to intricately regulate the expression of their virulence determinants by utilizing specific environmental cues. Here we show that a powerful repressor of Salmonella invasion, a cis-2 unsaturated long chain fatty acid, is present in the murine large intestine. Originally identified in Xylella fastidiosa as a diffusible signal factor for quorum sensing, this fatty acid directly interacts with HilD, the master transcriptional regulator of Salmonella, and prevents hilA activation, thus inhibiting Salmonella invasion. We further identify the fatty acid binding region of HilD and show it to be selective and biased in favour of signal factors with a cis-2 unsaturation over other intestinal fatty acids. Single mutation of specific HilD amino acids to alanine prevented fatty acid binding, thereby alleviating their repressive effect on invasion. Together, these results highlight an exceedingly sensitive mechanism used by Salmonella to colonize its host by detecting and exploiting specific molecules present within the complex intestinal environment.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bacterial Proteins / genetics
Bacterial Proteins / metabolism*
Carcinoma, Squamous Cell / metabolism
Carcinoma, Squamous Cell / microbiology
Carcinoma, Squamous Cell / pathology
Fatty Acids, Unsaturated / metabolism*
Gene Expression Regulation, Bacterial
Humans
Intestines / microbiology*
Intestines / physiology
Laryngeal Neoplasms / metabolism
Laryngeal Neoplasms / microbiology*
Laryngeal Neoplasms / pathology
Mice
Mice, Inbred C57BL
Salmonella Infections / metabolism
Salmonella Infections / microbiology*
Salmonella Infections / pathology
Salmonella typhimurium / genetics
Salmonella typhimurium / metabolism
Salmonella typhimurium / pathogenicity*
Trans-Activators / genetics
Trans-Activators / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Cells, Cultured
Virulence

Substances

Bacterial Proteins
Fatty Acids, Unsaturated
HilA protein, Salmonella
HilD protein, Salmonella typhimurium
Trans-Activators
Transcription Factors

Grants and funding

This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2016-10255 from the USDA National Institute of Food and Agriculture and by NIH/USDA NIFA Dual Purpose with Dual Benefit program; Grant No. 2014-67015-21697 to CA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.