The canonical long-chain fatty acid sensing machinery processes arachidonic acid to inhibit virulence in enterohemorrhagic escherichia coli

Melissa Ellermann, Angel G. Jimenez, Reed Pifer, Nestor Ruiz, Vanessa Sperandio

Research output: Contribution to journalArticlepeer-review

Abstract

The mammalian gastrointestinal tract is a complex biochemical organ that generates a diverse milieu of host-and microbe-derived metabolites. In this environ-ment, bacterial pathogens sense and respond to specific stimuli, which are integrated into the regulation of their virulence programs. Previously, we identified the transcription factor FadR, a long-chain fatty acid (LCFA) acyl coenzyme A (acyl-CoA) sensor, as a novel virulence regulator in the human foodborne pathogen enterohemorrhagic Escherichia coli (EHEC). Here, we demonstrate that exogenous LCFAs directly inhibit the locus of enterocyte effacement (LEE) pathogenicity island in EHEC through sensing by FadR. Moreover, in addition to LCFAs that are 18 carbons in length or shorter, we intro-duce host-derived arachidonic acid (C20:4) as an additional LCFA that is recognized by the FadR system in EHEC. We show that arachidonic acid is processed by the acyl-CoA synthetase FadD, which permits binding to FadR and decreases FadR affinity for its target DNA sequences. This interaction enables the transcriptional regulation of FadR-re-sponsive operons by arachidonic acid in EHEC, including the LEE. Finally, we show that arachidonic acid inhibits hallmarks of EHEC disease in a FadR-dependent manner, including EHEC attachment to epithelial cells and the formation of attaching and effacing lesions. Together, our findings delineate a molecular mechanism demonstrating how LCFAs can directly inhibit the virulence of an enteric bacterial pathogen. More broadly, our findings expand the repertoire of ligands sensed by the canonical LFCA sensing machinery in EHEC to include arachidonic acid, an important bioactive lipid that is ubiqui-tous within host environments.

Original languageEnglish (US)
Article numbere03247-20
Pages (from-to)1-17
Number of pages17
JournalmBio
Volume12
Issue number1
DOIs
StatePublished - 2021

Keywords

  • Arachidonic acid
  • Enterohemorrhagic E. coli (EHEC)
  • FadR
  • Fatty acid
  • Host-pathogen interactions
  • Infection
  • Locus of enterocyte effacement (LEE)
  • Omega 6
  • PUFA
  • Virulence regulation

ASJC Scopus subject areas

  • Microbiology
  • Virology

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