Abstract

EXCEED THE SPACE PROVIDED. E. coil 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. coil 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. coil K1 invasion is a complex process mediated by multiple E. coil invasion determinants, among which the 50-kDa protein encoded by ibeA is unique to E. coil 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. coil (GimA) containing 15 genes, which consist of four operons, ptnlPKC, cglDTEC, gcxKRCI and ibeRAT. IbeA is an important virulence factor contributing to E. coil Kl-induced invasion and apoptosis in BMEC and the 14 other genes may involve in energy metabolism. The regulatory protein IbeR carrying a _s4-interaction domain belongs to the NtrC/NifA family of transcriptional activators. It has been shown that anaerobic growth and glucose greatly enhanced E. coil K1 invasion of BMEC. Based on these results, we have hypothesized that the ibeA locus-mediated invasion and apoptosis are coordinate events in pathogenesis of E. coil K1 meningitis. Interactions between IbeA and its receptor induce cellular responses that are required for E. coil entry of BMECs. Invasion gene expression is regulated by the genetic island GimA including IbeR. Our hypothesis will be tested through the following Specific Aims. (1). To examine how lbeA contributes to E. coil K1 entry of human BMECs. (2). To further characterize the role of lbeA binding protein (s) in E. coil K1 invasion of human BMEC. (3). To determine how the ibeA locus (GimA) including tbeR contributes to regulation of E. coil K1 invasion gene expression. PERFORMANCE SITE ========================================Section End===========================================

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040635-08
Application #
6838712
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
2005-01-01
Budget End
2005-12-31
Support Year
8
Fiscal Year
2005
Total Cost
$260,400
Indirect Cost

  Institution

Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027

  Publications

Biasini, Fred J; De Jong, Desiree; Ryan, Sarah et al. (2015) Development of a 12 month screener based on items from the Bayley II Scales of Infant Development for use in Low Middle Income countries. Early Hum Dev 91:253-8
Long, Min; Huang, Sheng-He; Wu, Chun-Hua et al. (2012) Lipid raft/caveolae signaling is required for Cryptococcus neoformans invasion into human brain microvascular endothelial cells. J Biomed Sci 19:19
Huang, Sheng-He; Wu, Chun-Hua; Chang, Yun C et al. (2012) Cryptococcus neoformans-derived microvesicles enhance the pathogenesis of fungal brain infection. PLoS One 7:e48570
Huang, Sheng-He; Long, Min; Wu, Chun-Hua et al. (2011) Invasion of Cryptococcus neoformans into human brain microvascular endothelial cells is mediated through the lipid rafts-endocytic pathway via the dual specificity tyrosine phosphorylation-regulated kinase 3 (DYRK3). J Biol Chem 286:34761-9
Che, Xiaojuan; Chi, Feng; Wang, Lin et al. (2011) Involvement of IbeA in meningitic Escherichia coli K1-induced polymorphonuclear leukocyte transmigration across brain endothelial cells. Brain Pathol 21:389-404
Chi, Feng; Wang, Lin; Zheng, Xueye et al. (2011) Recruitment of ?7 nicotinic acetylcholine receptor to caveolin-1-enriched lipid rafts is required for nicotine-enhanced Escherichia coli K1 entry into brain endothelial cells. Future Microbiol 6:953-66
Huang, Sheng-He; Wu, Chu-Hua; Jiang, Shibo et al. (2011) HIV-1 gp41 ectodomain enhances Cryptococcus neoformans binding to human brain microvascular endothelial cells via gp41 core-induced membrane activities. Biochem J 438:457-66
Chi, Feng; Wang, Lin; Zheng, Xueye et al. (2011) Meningitic Escherichia coli K1 penetration and neutrophil transmigration across the blood-brain barrier are modulated by alpha7 nicotinic receptor. PLoS One 6:e25016
Chi, Feng; Jong, Timothy D; Wang, Lin et al. (2010) Vimentin-mediated signalling is required for IbeA+ E. coli K1 invasion of human brain microvascular endothelial cells. Biochem J 427:79-90
Chi, Feng; Wang, Ying; Gallaher, Timothy K et al. (2009) Identification of IbeR as a stationary-phase regulator in meningitic Escherichia coli K1 that carries a loss-of-function mutation in rpoS. J Biomed Biotechnol 2009:520283

Showing the most recent 10 out of 17 publications