Vaccine value profile for enterotoxigenic Escherichia coli (ETEC)

Khalil, Ibrahim; Anderson, John D.; Bagamian, Karoun H.; Baqar, Shahida; Giersing, Birgitte; Hausdorff, William P.; Marshall, Caroline; Porter, Chad K.; Walker, Richard I.; Bourgeois, A. Louis

doi:10.1016/j.vaccine.2023.02.011

Cited by 7 publications

(16 citation statements)

References 80 publications

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“…Given the persistent and pervasive impacts of ETEC infections, these pathogens have remained a high priority for vaccine development 14–16 . Efforts to identify novel surface-expressed molecules that might be targeted in ETEC vaccine development led to the identification of the plasmid-borne etpBAC two-partner secretion (TPS) locus responsible for export of EtpA, an extracellular adhesin 17 .…”

Section: Introductionmentioning

confidence: 99%

Repeat modules and N-linked glycans define structure and antigenicity of a critical enterotoxigenicE. coli adhesin

Berndsen,

Akhtar,

Thapa

et al. 2024

Preprint

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EnterotoxigenicEscherichia coli(ETEC) cause hundreds of millions of cases of infectious diarrhea annually, predominantly in children from low-middle income regions. Notably, in children, as well as human volunteers challenged with ETEC, diarrheal severity is significantly increased severity in blood group A (bgA) individuals. EtpA, is a secreted glycoprotein adhesin that functions as a blood group A lectin to promote critical interactions between ETEC and blood group A glycans on intestinal epithelia for effective bacterial adhesion and toxin delivery. EtpA is highly immunogenic resulting in robust antibody responses following natural infection and experimental challenge of human volunteers with ETEC. To understand how EtpA directs ETEC-blood group A interactions and stimulates adaptive immunity, we mutated EtpA, mapped its glycosylation by mass-spectrometry (MS), isolated polyclonal (pAbs) and monoclonal antibodies (mAbs) from vaccinated mice and ETEC-infected human volunteers, and determined structures of antibody-EtpA complexes by cryo-electron microscopy. Both bgA and mAbs that inhibited EtpA-bgA interactions and ETEC adhesion, bound to the C-terminal repeat domain highlighting this region as crucial for ETEC pathogen-host interaction. MS analysis uncovered extensive and heterogeneous N-linked glycosylation of EtpA and cryo-EM structures revealed that mAbs directly engage these unique glycan containing epitopes. Finally, electron microscopy-based polyclonal epitope mapping revealed antibodies targeting numerous distinct epitopes on N and C-terminal domains, suggesting that EtpA vaccination generates responses against neutralizing and decoy regions of the molecule. Collectively, we anticipate that these data will inform our general understanding of pathogen-host glycan interactions and adaptive immunity relevant to rational vaccine subunit design.

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Section: Introductionmentioning

confidence: 99%

Repeat modules and N-linked glycans define structure and antigenicity of a critical enterotoxigenicE. coli adhesin

Berndsen,

Akhtar,

Thapa

et al. 2024

Preprint

Self Cite

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“…ETEC and enteropathogenic E. coli (EPEC) infections in low- and middle-income countries (LMICs) cause disease outbreaks requiring interventions. ETECs are estimated to cause about 220 million cases of diarrhoea, 75 million affecting children under 5 years of age [ 8 ]. The high level of mortality, especially in children, makes the development of the ETEC vaccine the WHO’s primary strategic goal [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…ETECs are estimated to cause about 220 million cases of diarrhoea, 75 million affecting children under 5 years of age [ 8 ]. The high level of mortality, especially in children, makes the development of the ETEC vaccine the WHO’s primary strategic goal [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

adhesiomeR: a tool for Escherichia coli adhesin classification and analysis

Sidorczuk,

Burdukiewicz,

Cerk

et al. 2024

BMC Genomics

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Adhesins are crucial factors in the virulence of bacterial pathogens such as Escherichia coli. However, to date no resources have been dedicated to the detailed analysis of E. coli adhesins. Here, we provide adhesiomeR software that enables characterization of the complete adhesin repertoire, termed the adhesiome. AdhesiomeR incorporates the most comprehensive database of E. coli adhesins and facilitates an extensive analysis of adhesiome. We demonstrate that adhesiomeR achieves 98% accuracy when compared with experimental analyses. Based on analysis of 15,000 E. coli genomes, we define novel adhesiome profiles and clusters, providing a nomenclature for a unified comparison of E. coli adhesiomes.

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“…ETEC also remains the leading cause of diarrhea among travelers and military personnel visiting endemic areas. The WHO recently reaffirmed that ETEC is a vaccine priority, and, given its recognition as a significant Anti-Microbial Resistance (AMR) threat, public health stakeholders have urged the acceleration of the development of a vaccine [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%