Childhood diarrhea leads to 2 million deaths every year among children less than 5 years of age mainly in underserved countries. E. coli pathogens are believed to be the second most common cause of death after Rotavirus. Six categories of diarrheagenic E. coli have been known to cause diarrhea, yet, recent studies by our group have identified a new diarrheagenic category designated localized adherent E. coli (LAEC) that is significantly associated with childhood diarrhea in Colombia, South America. The long term goal of this study is to understand the epidemiology and the molecular mechanisms of pathogenesis of this new LAEC emergent pathogen. The first specific aim proposes to evaluate the frequency and association of LAEC with childhood diarrhea by conducting two international multicenter case-control studies. We hypothesize that LAEC is associated with childhood diarrhea in children less than 5 years of age living in developing countries. The second specific aim will explain how LAEC virulence factors are essential to cause disease in a piglet model of human infection. We hypothesize that the type IV bundle-forming pilus and a novel type III secretion system directing bacterial-cell invasion are directly associated with the pathogenesis of LAEC diarrhea. The last specific aim will conduct genome DNA sequencing analysis of LAEC strains to identify the genetic elements that resulted in the emergence of LAEC as a pathogen. We hypothesize that LAEC shares in common well defined virulence genes that were acquired by horizontal gene transfer. This project if significant because it will bring fundamental knowledge on the epidemiology, genetics, and pathogenesis of LAEC and will generate molecular biology tools to facilitate future studies on LAEC diarrhea epidemiology, prevention measures and vaccine development research.

Public Health Relevance

Diarrheagenic E. coli are the second most common cause of diarrhea in children less than 5 years of age leading to high mortality in children from underserved countries. This study is relevant because it will generate fundamental knowledge on the epidemiology, genetics and pathogenesis of an emergent pathogen, designated localized adherence E. coli (LAEC), recently recognized as the second most common diarrheagenic E. coli agent in Colombian children. The significance of this work is that the molecular tools and knowledge generated in this study will allow future studies on the epidemiology of LAEC worldwide, on the mechanisms of pathogenicity at the molecular level, and on the development of prevention strategies, including vaccine development, to control childhood diarrheal by this organism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI095346-02
Application #
8597997
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Baqar, Shahida
Project Start
2012-12-15
Project End
2017-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$325,771
Indirect Cost
$95,659
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Guerra, Julio A; Romero-Herazo, Yesenia C; Arzuza, Octavio et al. (2014) Phenotypic and genotypic characterization of enterotoxigenic Escherichia coli clinical isolates from northern Colombia, South America. Biomed Res Int 2014:236260