E. coli K1 is the most common gram-negative organism causing neonatal meningitis. One of the least understood issues in the pathogenesis of this disease is how circulating E. coli K1 crosses the blood-brain barrier (BBB) to cause brain injury. We have demonstrated in the in vitro and in vivo models of the BBB that E. coli K1 invasion is a complex process mediated by multiple E. coli invasion determinants, among which the 50-kDa protein encoded by ibeA is unique to E. coli K1. A bovine IbeA-binding protein (IbeABP) has been isolated by IbeA-affinity chromatography from brain microvascular endothelial cells (BMEC). The ibeA locus is a genetic island of meningitic E. coli (GimA) containing 15 genes, which consist of four operons, ptnlPKC, cglDTEC, gcxKRCI and ibeRAT. IbeA is an important virulence factor contributing to E. coli K1-mediated invasion in BMEC and the 14 other genes may involve in energy metabolism. The regulatory protein IbeR carrying an as4-interaction domain belongs to the NtrC/NifA family of transcriptional activators. It has been shown that anaerobic growth and glucose greatly enhanced E. coli K1 invasion of BMEC. Based on these results, we have hypothesized that the ibeA locus-mediated invasion and energy metabolism are coordinate events in pathogenesis of E. coli K1 meningitis. Interactions between IbeA and its receptor induce cellular responses that are required for E. coli entry of BMECs. Invasion gene expression is regulated by the genetic island GimA including IbeR and environmental signals. Our hypothesis will be tested through the following Specific Aims. (1). To examine how IbeA contributes to E. coil K1 entry of human BMECs. (2). To further characterize the role of IbeABP in E. coil K1 invasion of human BMEC. (3). To determine how E. coil K1 invasion gene expression is regulated by the ibeA locus (GimA) including IbeR and environmental signals (glucose and oxygen tension).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI040635-06A2
Application #
6687401
Study Section
Special Emphasis Panel (ZRG1-BM-1 (05))
Program Officer
Korpela, Jukka K
Project Start
1997-07-01
Project End
2007-12-31
Budget Start
2003-07-01
Budget End
2003-12-31
Support Year
6
Fiscal Year
2003
Total Cost
$130,200
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
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