{'fraction_non_alphanumeric': 0.018072289156626505, 'fraction_numerical': 0.0018825301204819277, 'mean_word_length': 5.709595959595959, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Enterotoxigenic E. coli virulence gene regulation in human infections

Significance Bacterial pathogens must sense cues in the host environment and adapt with appropriate transcriptional responses to cause infections. Although identifying global transcriptional changes in a pathogen during infections would reveal these mechanisms of success, such work in human infections is difficult and rare. Here we use samples from a controlled human model of enterotoxigenic Escherichia coli (ETEC) infection to identify ETEC’s global transcriptional response to the human host. We found ETEC senses environmental oxygen to coordinate virulence gene expression during human infections via the transcriptional regulator FNR, and that FNR regulates biofilm formation in ETEC. This work identified a global regulator of virulence genes in ETEC where toxin and adhesin expression is coordinated with pathogen proximity to the epithelium. 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.