Abstract
We have reported that transcription of a hypothetical small open reading frame (orf60) in enteroaggregative E. coli (EAEC) strain 042 is impaired after mutation of aggR, which encodes a global virulence activator. We have also reported that the cryptic orf60 locus was linked to protection against EAEC diarrhea in two epidemiologic studies. Here, we report that the orf60 product acts as a negative regulator of aggR itself. The orf60 protein product lacks homology to known repressors, but displays 44–100% similarity to at least fifty previously undescribed small (<10 kDa) hypothetical proteins found in many gram negative pathogen genomes. Expression of orf60 homologs from enterotoxigenic E. coli (ETEC) repressed the expression of the AraC-transcriptional ETEC regulator CfaD/Rns and its regulon in ETEC strain H10407. Complementation in trans of EAEC 042orf60 by orf60 homologs from ETEC and the mouse pathogen Citrobacter rodentium resulted in dramatic suppression of aggR. A C. rodentium orf60 homolog mutant showed increased levels of activator RegA and increased colonization of the adult mouse. We propose the name Aar (AggR-activated regulator) for the clinically and epidemiologically important orf60 product in EAEC, and postulate the existence of a large family of homologs among pathogenic Enterobacteriaceae and Pasteurellaceae. We propose the name ANR (AraC Negative Regulators) for this family.
Highlights
Enteroaggregative Escherichia coli (EAEC) is a diarrheagenic pathotype linked to traveler’s diarrhea, foodborne outbreaks and sporadic diarrhea in industrialized and developing countries [1,2,3,4]
Virulence gene expression in EAEC is activated in coordinate fashion by a regulator called AggR, a member of the AraC/XylS family of bacterial transcription factors [7,8,9]; AggR is most closely related to the CfaD/Rns activator of enterotoxigenic E. coli (ETEC) [10], RegA in C. rodentium [11] and PerA in enteropathogenic E. coli (EPEC) [12,13]
Members of this regulator family in enteroaggregative (EAEC) and enterotoxigenic E. coli (ETEC) and in Citrobacter rodentium downregulate the expression of positive regulator partners AggR, CfaD/Rns and RegA, respectively, all members of the AraC/XylS family of regulators
Summary
Enteroaggregative Escherichia coli (EAEC) is a diarrheagenic pathotype linked to traveler’s diarrhea, foodborne outbreaks and sporadic diarrhea in industrialized and developing countries [1,2,3,4]. In an effort to understand the highly mosaic character of the EAEC genome and its relationship to endemic diarrhea in developing countries, we scored the presence of AggRdependent and AggR-independent putative virulence genes among collections of EAEC strains from children under 5 years of age with diarrhea in Mali [15] and Brazil [16]. In both studies, we were struck by the strong and consistent negative association between the presence of orf60/61 and diarrhea. Given compelling data favoring some important role for cryptic locus orf60/61 in EAEC epidemiology, we undertook a thorough investigation of its role in pathogenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
