This work focuses on enterotoxigenic Escherichia coli (ETEC), globally the most common bacterial cause of serious diarrheal illness. These illnesses threaten the lives of many children in poor regions of the world where sanitation and clean water are limited. While it has long been known that prior infections with these organisms offer protection against later infection, the nature of the protection is not known. The long-term goal o these studies is to address very basic questions that have eluded ETEC investigators trying to develop vaccines for these organisms: 1.To what proteins do infected people mount antibody responses after infection? 2. Which of these responses appear to be associated with protection against ETEC? 3. Can we show that these proteins trigger protective immune responses in a vaccine? Studies to date have shown us that the immune response following ETEC infection is actually quite complicated, with recognition of many proteins. Some novel proteins that are not part of vaccines currently being tested could be added to improve the coverage and function of these vaccines. The basic goals of this proposal are to accelerate the discovery of novel protective proteins and to translate their use into effective ETEC vaccine components. Addressing these fundamental questions will fill important gaps in our understanding of protective immune responses that develop following ETEC infections, and permit a more rational approach to development of a broadly protective vaccine for these pathogens of global importance.

Public Health Relevance

Enterotoxigenic Escherichia coli (ETEC) are responsible for millions of infections and hundreds of thousands of deaths due to diarrhea annually, particularly among young children in developing countries. This project is designed to accelerate development of a vaccine to prevent these infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI089894-08
Application #
9116756
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Baqar, Shahida
Project Start
2010-07-01
Project End
2020-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Kumar, Pardeep; Kuhlmann, F Matthew; Chakraborty, Subhra et al. (2018) Enterotoxigenic Escherichia coli-blood group A interactions intensify diarrheal severity. J Clin Invest 128:3298-3311
Brown, Jeffrey W; Badahdah, Arwa; Iticovici, Micah et al. (2018) A Role for Salivary Peptides in the Innate Defense Against Enterotoxigenic Escherichia coli. J Infect Dis 217:1435-1441
Zhu, Yuehui; Luo, Qingwei; Davis, Sierra M et al. (2018) Molecular Determinants of Enterotoxigenic Escherichia coli Heat-Stable Toxin Secretion and Delivery. Infect Immun 86:
Sheikh, Alaullah; Rashu, Rasheduzzaman; Begum, Yasmin Ara et al. (2017) Highly conserved type 1 pili promote enterotoxigenic E. coli pathogen-host interactions. PLoS Negl Trop Dis 11:e0005586
Fleckenstein, James M (2017) Providing Structure to Enterotoxigenic Escherichia coli Vaccine Development. J Infect Dis 216:1-3
Hazen, Tracy H; Michalski, Jane; Luo, Qingwei et al. (2017) Comparative genomics and transcriptomics of Escherichia coli isolates carrying virulence factors of both enteropathogenic and enterotoxigenic E. coli. Sci Rep 7:3513
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Fleckenstein, James M; Rasko, David A (2016) Overcoming Enterotoxigenic Escherichia coli Pathogen Diversity: Translational Molecular Approaches to Inform Vaccine Design. Methods Mol Biol 1403:363-83
Luo, Qingwei; Vickers, Tim J; Fleckenstein, James M (2016) Immunogenicity and Protective Efficacy against Enterotoxigenic Escherichia coli Colonization following Intradermal, Sublingual, or Oral Vaccination with EtpA Adhesin. Clin Vaccine Immunol 23:628-37

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