Abstract
Although enteroaggregative E. coli (EAEC) has been implicated as a common cause of diarrhea in multiple settings, neither its essential genomic nature nor its role as an enteric pathogen are fully understood. The current definition of this pathotype requires demonstration of cellular adherence; a working molecular definition encompasses E. coli which do not harbor the heat-stable or heat-labile toxins of enterotoxigenic E. coli (ETEC) and harbor the genes aaiC, aggR, and/or aatA. In an effort to improve the definition of this pathotype, we report the most definitive characterization of the pan-genome of EAEC to date, applying comparative genomics and functional characterization on a collection of 97 EAEC strains isolated in the course of a multicenter case-control diarrhea study (Global Enteric Multi-Center Study, GEMS). Genomic analysis revealed that the EAEC strains mapped to all phylogenomic groups of E. coli. Circa 70% of strains harbored one of the five described AAF variants; there were no additional AAF variants identified, and strains that lacked an identifiable AAF generally did not have an otherwise complete AggR regulon. An exception was strains that harbored an ETEC colonization factor (CF) CS22, like AAF a member of the chaperone-usher family of adhesins, but not phylogenetically related to the AAF family. Of all genes scored, sepA yielded the strongest association with diarrhea (P = 0.002) followed by the increased serum survival gene, iss (p = 0.026), and the outer membrane protease gene ompT (p = 0.046). Notably, the EAEC genomes harbored several genes characteristically associated with other E. coli pathotypes. Our data suggest that a molecular definition of EAEC could comprise E. coli strains harboring AggR and a complete AAF(I-V) or CS22 gene cluster. Further, it is possible that strains meeting this definition could be both enteric bacteria and urinary/systemic pathogens.
Highlights
Enteroaggregative E. coli (EAEC) has been implicated as a common cause of acute and persistent diarrhea [1,2] and as a cause of linear growth faltering among children in low-income countries [3]
We identified a genetic signature of EAEC which could comprise of E. coli strains harboring the EAEC transcriptional activator and its adhesin dependent factors
We found that EAEC strains harbor additional putative virulence genes previously reported in extraintestinal pathogenic E. coli (ExPEC) and, strains meeting the re-definition could be both enteric bacteria and urinary/systemic pathogens
Summary
Enteroaggregative E. coli (EAEC) has been implicated as a common cause of acute and persistent diarrhea [1,2] and as a cause of linear growth faltering among children in low-income countries [3]. EAEC strains often harbor a variable number of serine protease autotransporters of Enterobacteriaceae (SPATEs) [10], which are implicated in immune evasion, mucosal damage, secretogenicity, and colonization [24]. None of these AggR-dependent or AggR-independent factors are found in all EAEC isolates and, no single factor has ever been consistently implicated epidemiologically in EAEC diarrhea [7,8,25]. Strains that adhere to HEp-2 cells but do not carry AggR-regulated genes have never been evaluated in human volunteer studies, and are of uncertain pathogenicity
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