Despite appropriate antibiotics, CNS infections with Escherichia coli continue to cause significant morbidity and mortality. The lack of knowledge concerning the pathogenesis of this infection contributes to limited improvements in interventions. Successful transversal of E. coli across the blood brain barrier requires S. fimbriae for binding and OmpA for invasion. Both of these interact with epitopes (NeuAc alpha 2,3-galactose and G1cNAc beta 1, 4G1cNAc) on a novel 65 Da sialoglycoprotein on brain microvascular endothelium (BMEC). To date, the investigator has been screening a human BMEC cDNA library with antibodies against the 65 Da protein and has identified 6 positive cDNA clones. The goals of the current proposal are to 1) characterize the gene encoding the 65 Da glycoprotein involved with E. coli binding 2) to use recombinant protein to further investigate bacteria (host interactions in transfected CHO cells and in blocking experiments in a rat meningitis model and 3) to determine if E. coli binding and invasion of BMEC is due to the glycoprotein by using anti-sense oligonucleotides to inhibit gene expression in BMEC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI040567-02
Application #
2633577
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Krishnan, Subramanian; Chang, Alexander C; Stoltz, Brian M et al. (2016) Escherichia coli K1 Modulates Peroxisome Proliferator-Activated Receptor ? and Glucose Transporter 1 at the Blood-Brain Barrier in Neonatal Meningitis. J Infect Dis 214:1092-104
Doran, Kelly S; Fulde, Marcus; Gratz, Nina et al. (2016) Host-pathogen interactions in bacterial meningitis. Acta Neuropathol 131:185-209
Krishnan, Subramanian; Chang, Alexander C; Hodges, Jacqueline et al. (2015) Serotype O18 avian pathogenic and neonatal meningitis Escherichia coli strains employ similar pathogenic strategies for the onset of meningitis. Virulence 6:777-86
Krishnan, Subramanian; Prasadarao, Nemani V (2014) Identification of minimum carbohydrate moiety in N-glycosylation sites of brain endothelial cell glycoprotein 96 for interaction with Escherichia coli K1 outer membrane protein A. Microbes Infect 16:540-52
Shanmuganathan, Muthusamy V; Krishnan, Subramanian; Fu, Xiaowei et al. (2014) Escherichia coli K1 induces pterin production for enhanced expression of Fc? receptor I to invade RAW 264.7 macrophages. Microbes Infect 16:134-41
Krishnan, Subramanian; Liu, Fan; Abrol, Ravinder et al. (2014) The interaction of N-glycans in Fc? receptor I ?-chain with Escherichia coli K1 outer membrane protein A for entry into macrophages: experimental and computational analysis. J Biol Chem 289:30937-49
Krishnan, Subramanian; Shanmuganathan, Muthusamy V; Behenna, Douglas et al. (2014) Angiotensin II receptor type 1--a novel target for preventing neonatal meningitis in mice by Escherichia coli K1. J Infect Dis 209:409-19
Shanmuganathan, Muthusamy V; Krishnan, Subramanian; Fu, Xiaowei et al. (2013) Attenuation of biopterin synthesis prevents Escherichia coli K1 invasion of brain endothelial cells and the development of meningitis in newborn mice. J Infect Dis 207:61-71
Ahn, Kwang H; Scott, Caitlin E; Abrol, Ravinder et al. (2013) Computationally-predicted CB1 cannabinoid receptor mutants show distinct patterns of salt-bridges that correlate with their level of constitutive activity reflected in G protein coupling levels, thermal stability, and ligand binding. Proteins 81:1304-17
Krishnan, Subramanian; Chen, Shuang; Turcatel, Gianluca et al. (2013) Regulation of Toll-like receptor 2 interaction with Ecgp96 controls Escherichia coli K1 invasion of brain endothelial cells. Cell Microbiol 15:63-81

Showing the most recent 10 out of 39 publications