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 some ETEC are clearly associated with development of cholera- like diarrhea, basic molecular mechanisms underlying severe illness remain undefined. The long-term goal of these studies is to address basic questions that can inform our understanding of acute illness and more chronic sequelae that may impact or approach to development of vaccines for these organisms: ? ?Why are individuals with blood group A more susceptible to severe infections cause by ETEC ?? ? ?How does ETEC or its toxins alter intestinal surfaces to promote infection?? ? ?Are ETEC particularly well-equipped to promote these interactions?? ? ?Are there other antigens that interact with host cells to promote infections?? Studies to date have shown us that the pathogenesis of ETEC infection is actually quite complicated, potentially involving many proteins. Novel proteins that are not part of vaccines currently being tested could be added to improve the coverage and function of these vaccines. Understanding disease susceptibility on a molecular level can permit us to protect individuals at the highest risk. Addressing these fundamental questions will fill important gaps in our understanding of ETEC interactions with the intestine as well as cellular responses that develop following ETEC infections. Collectively these studies should 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. These illnesses also contribute substantially to chronic sequelae including malnutrition, growth delays and altered intellectual development. This project is designed to characterize ETEC interactions with the intestine to guide novel approaches to treatment and vaccine development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI126887-04
Application #
9693123
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Baqar, Shahida
Project Start
2016-06-14
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
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
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:
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
Sahl, Jason W; Sistrunk, Jeticia R; Baby, Nabilah Ibnat et al. (2017) Insights into enterotoxigenic Escherichia coli diversity in Bangladesh utilizing genomic epidemiology. Sci Rep 7:3402
Kumar, Pardeep; Kuhlmann, F Matthew; Bhullar, Kirandeep et al. (2016) Dynamic Interactions of a Conserved Enterotoxigenic Escherichia coli Adhesin with Intestinal Mucins Govern Epithelium Engagement and Toxin Delivery. Infect Immun 84:3608-3617