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Host-derived CEACAM-laden vesicles engage enterotoxigenic E. coli for elimination and toxin neutralization.

ABSTRACT: Enterotoxigenic Escherichia coli (ETEC) cause hundreds of millions of diarrheal illnesses annually ranging from mildly symptomatic cases to severe, life-threatening cholera-like diarrhea. Although ETEC are associated with long-term sequelae including malnutrition, the acute diarrheal illness is largely self-limited. Recent studies indicate that in addition to causing diarrhea, the ETEC heat-labile toxin (LT) modulates the expression of many genes in intestinal epithelia, including carcinoembryonic cell adhesion molecules (CEACAMs) which ETEC exploit as receptors, enabling toxin delivery. Here however, we demonstrate that LT also enhances the expression of CEACAMs on extracellular vesicles (EV) shed by intestinal epithelia and that CEACAM-laden EV increase in abundance during human infections, mitigate pathogen-host interactions, scavenge free ETEC toxins, and accelerate ETEC clearance from the gastrointestinal tract. Collectively, these findings indicate that CEACAMs play a multifaceted role in ETEC pathogen-host interactions, transiently favoring the pathogen, but ultimately contributing to innate responses that extinguish these common infections.

SUBMITTER: Sheikh A

PROVIDER: S-EPMC11291149 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Host-derived CEACAM-laden vesicles engage enterotoxigenic <i>E. coli</i> for elimination and toxin neutralization.

Sheikh Alaullah A Ganguli Debayan D Vickers Tim J TJ Singer Bernhard B Foulke-Abel Jennifer J Akhtar Marjahan M Khatoon Nazia N Setu Bipul B Basu Supratim S Harro Clayton C Maier Nicole N Beatty Wandy L WL Chakraborty Subhra S Bhuiyan Tafiqur R TR Qadri Firdausi F Donowitz Mark M Fleckenstein James M JM

bioRxiv : the preprint server for biology 20240724

Enterotoxigenic <i>Escherichia coli</i> (ETEC) cause hundreds of millions of diarrheal illnesses annually ranging from mildly symptomatic cases to severe, life-threatening cholera-like diarrhea. Although ETEC are associated with long-term sequelae including malnutrition, the acute diarrheal illness is largely self-limited. Recent studies indicate that in addition to causing diarrhea, the ETEC heat-labile toxin (LT) modulates the expression of many genes in intestinal epithelia, including carcino ...[more]

PMID: 39091797

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Project description:Introduction. Diarrhoeagenic Escherichia coli (DEC) pathotypes are defined by genes located on mobile genetic elements, and more than one definitive pathogenicity gene may be present in the same strain. In August 2022, UK Health Security Agency (UKHSA) surveillance systems detected an outbreak of hybrid Shiga toxin-producing E. coli/enterotoxigenic E. coli (STEC-ETEC) serotype O101:H33 harbouring both Shiga toxin (stx) and heat-stable toxin (st).Gap statement. These hybrid strains of DEC are a public health concern, as they are often associated with enhanced pathogenicity. However, little is known about their epidemiology, clinical significance and associated public health burden.Aim. The aim of this study was to describe the microbiology, epidemiology and genomic analysis of this novel hybrid serotype in the context of the STEC-ETEC strains in the UKHSA archive.Methodology. From 2014 to 2023, STEC isolated from faecal specimens testing positive for STEC by PCR were sequenced on the NextSeq 1000 short read platform and a subset were selected for long read nanopore sequencing. Genomes were analysed to determine serotype, stx subtype, DEC pathogenicity genes and antimicrobial resistance determinants.Results. There were 162 STEC-ETEC strains isolated between 2014 and 2023, of which 117/162 were human clinical isolates and 45 were of food or animal origin. An average of 16 STEC-ETEC strains were identified each year, exhibiting a range of different stx subtypes, the most common profiles being stx2g,st (n=65, 40%) and stx2a,st (n=48, 30%). The most common sequence types were ST329 and ST200 (n=24 each), and the most frequently detected serotype was O187:H28 (n=25). Nine cases of genetically linked STEC-ETEC O101:H33, stx1a,st were detected between 8 August and 21 September 2022. Although the temporal and geographical distribution of the cases was characteristic of a foodborne outbreak, the contaminated vehicle was not identified.Conclusions. Phylogenetic analysis and long-read sequencing of the outbreak strain provided insight into the stepwise acquisition of st and stx and the evolutionary history of STEC-ETEC pathotypes. The integration of epidemiological data and whole-genome sequencing for routine surveillance of gastrointestinal pathogens is key to understanding the emergence of zoonotic hybrid DEC pathotypes and monitoring foodborne threats to public health.

Project description:Enterotoxigenic Escherichia coli (ETEC) strains producing heat-labile toxin (LT) and/or heat-stable toxin (STa) are a top cause of children's diarrhea and travelers' diarrhea. Holotoxin-structured GM1-binding LT is a strong immunogen and an effective adjuvant, and can serve a carrier or a platform for multivalent vaccine development. However, the significance of peptide domains or epitopes of LT particularly enzymatic LTA subunit in association with LT enterotoxicity and immunogenicity has not been characterized. In this study, we identified B-cell epitopes in silico from LTA subunit and examined epitopes for immunogenicity and association with LT enterotoxicity. Epitopes identified from LTA subunit were individually fused to a modified chicken ovalbumin carrier protein, and each epitope-ovalbumin fusion was used to immunize mice. Data showed all 11 LTA epitopes were immunogenic; epitope 7 (105SPHPYEQEVSA115) induced greater titers of anti-LT antibodies which neutralized LT enterotoxicity more effectively. To examine these epitopes for the significance in LT enterotoxicity, we constructed LT mutants by substituting each of 10 epitopes at the toxic A1 domain of LTA subunit with a foreign epitope and examined LT mutants for enterotoxicity and GM1-binding activity. Data showed that LT mutants exhibited no enterotoxicity but retained GM1-binding activity. The results from this study indicated that while not all immunodominant LTA epitopes were neutralizing, LT mutants with an individual epitope substituted lost enterotoxicity but retained GM1-binding activity. These results provided additional information to understand LT immunogenicity and enterotoxicity and suggested the potential application of LT platform for multivalent vaccines against ETEC diarrhea and other diseases.IMPORTANCE No vaccine is licensed for enterotoxigenic Escherichia coli (ETEC) strains, which remain a leading cause of diarrhea in children from developing countries and international travelers. GM1-binding heat-labile toxin (LT) which is a key virulence factor of ETEC diarrhea is a strong vaccine antigen and a self-adjuvant. LT can also serve a backbone or platform for MEFA (multiepitope fusion antigen), a newly developed structural vaccinology technology, to present heterogeneous epitopes (by replacing LT epitopes) and to mimic epitope antigenicity for development of broadly protective vaccines. Data from this study identified neutralizing LT epitopes and demonstrated that substitution of LT epitopes eliminated LT enterotoxicity without altering GM1-binding activity, suggesting LT is potentially a versatile MEFA platform to present heterogeneous epitopes for multivalent vaccines against ETEC and other pathogens.

Dataset Information

Host-derived CEACAM-laden vesicles engage enterotoxigenic E. coli for elimination and toxin neutralization.

Publications

Host-derived CEACAM-laden vesicles engage enterotoxigenic <i>E. coli</i> for elimination and toxin neutralization.

Similar Datasets

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