Enterotoxigenic E. Coli virulence gene regulation in human infections

Alexander A. Crofts, Simone M. Giovanetti, Erica J. Rubin, Frédéric M. Poly, Ramiro L. Gutiérrez, Kawsar R. Talaat, Chad K. Porter, Mark S. Riddle, Barbara DeNearing, Jessica Brubaker, Milton Maciel, Ashley N. Alcala, Subhra Chakraborty, Michael G. Prouty, Stephen J. Savarino, Bryan W. Davies, M. Stephen Trent

Research output: Contribution to journalArticlepeer-review

Abstract

Enterotoxigenic Escherichia coli (ETEC) is a global diarrheal pathogen that utilizes adhesins and secreted enterotoxins to cause disease in mammalian hosts. Decades of research on virulence factor regulation in ETEC has revealed a variety of environmental factors that influence gene expression, including bile, pH, bicarbonate, osmolarity, and glucose. However, other hallmarks of the intestinal tract, such as low oxygen availability, have not been examined. Further, determining how ETEC integrates these signals in the complex host environment is challenging. To address this, we characterized ETEC's response to the human host using samples from a controlled human infection model. We found ETEC senses environmental oxygen to globally influence virulence factor expression via the oxygen-sensitive transcriptional regulator fumarate and nitrate reduction (FNR) regulator. In vitro anaerobic growth replicates the in vivo virulence factor expression profile, and deletion of fnr in ETEC strain H10407 results in a significant increase in expression of all classical virulence factors, including the colonization factor antigen I (CFA/I) adhesin operon and both heat-stable and heat-labile enterotoxins. These data depict a model of ETEC infection where FNR activity can globally influence virulence gene expression, and therefore proximity to the oxygenated zone bordering intestinal epithelial cells likely influences ETEC virulence gene expression in vivo. Outside of the host, ETEC biofilms are associated with seasonal ETEC epidemics, and we find FNR is a regulator of biofilm production. Together these data suggest FNR-dependent oxygen sensing in ETEC has implications for human infection inside and outside of the host.

Original languageEnglish (US)
Pages (from-to)E8968-E8976
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number38
DOIs
StatePublished - Sep 18 2018

Keywords

  • Cfa
  • ETEC
  • Enterotoxigenic E. Coli
  • FNR
  • Toxin

ASJC Scopus subject areas

  • General

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