Abstract
Some enterotoxigenic Escherichia coli (ETEC) produce a type II heat-labile enterotoxin (LT-II) that activates adenylate cyclase in susceptible cells but is not neutralized by antisera against cholera toxin or type I heat-labile enterotoxin (LT-I). LT-I variants encoded by plasmids in ETEC from humans and pigs have amino acid sequences that are ≥95% identical. In contrast, LT-II toxins are chromosomally encoded and are much more diverse. Early studies characterized LT-IIa and LT-IIb variants, but a novel LT-IIc was reported recently. Here we characterized the LT-II encoding loci from 48 additional ETEC isolates. Two encoded LT-IIa, none encoded LT-IIb, and 46 encoded highly related variants of LT-IIc. Phylogenetic analysis indicated that the predicted LT-IIc toxins encoded by these loci could be assigned to 6 subgroups. The loci corresponding to individual toxins within each subgroup had DNA sequences that were more than 99% identical. The LT-IIc subgroups appear to have arisen by multiple recombinational events between progenitor loci encoding LT-IIc1- and LT-IIc3-like variants. All loci from representative isolates encoding the LT-IIa, LT-IIb, and each subgroup of LT-IIc enterotoxins are preceded by highly-related genes that are between 80 and 93% identical to predicted phage lysozyme genes. DNA sequences immediately following the B genes differ considerably between toxin subgroups, but all are most closely related to genomic sequences found in predicted prophages. Together these data suggest that the LT-II loci are inserted into lambdoid type prophages that may or may not be infectious. These findings raise the possibility that production of LT-II enterotoxins by ETEC may be determined by phage conversion and may be activated by induction of prophage, in a manner similar to control of production of Shiga-like toxins by converting phages in isolates of enterohemmorhagic E. coli.
Highlights
Enterotoxigenic Escherichia coli (ETEC) are the most common cause of bacterial diarrhea amongst travelers and overseas military personnel [1]
In this study we developed PCR-based methods to isolate and characterize the LTII loci in 48 additional type II ETEC isolates from humans (20%), animals (60%) and food (20%) sources, and we found that loci encoding labile enterotoxin (LT)-IIa and LT-IIb were very uncommon among the isolates in our collection
It includes the type strains for LT-IIa (SA53) and LT-IIb (T2-41)
Summary
Enterotoxigenic Escherichia coli (ETEC) are the most common cause of bacterial diarrhea amongst travelers and overseas military personnel [1] They cause significant mortality and morbidity among infants in the developing world, with estimates of 280–650 million cases reported for children under five and up to 800,000 fatalities a year [2,3]. A second type II enterotoxin (LT-IIb) and the operon that encodes it in an ETEC isolate from a cooked beef sample was subsequently characterized [10]. The crystal structures of CT, LT-I and LT-IIb holotoxins reveal that their folds are very similar [11] All members of this family are excellent adjuvants and have strong immunomodulatory properties that vary between toxins [12] that may aid in vaccine design and development. Isolation and characterization of additional novel variants of enterotoxins may be useful in expanding the repertoire of immunomodulatory enterotoxins
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