Microbial traversal of the blood-brain barrier is required for the development of central nervous system infection, but the underlying mechanisms remain incompletely understood. The blood-brain barrier is a structural and functional barrier that is formed by brain microvascular endothelial cells and protects the brain from any microorganisms circulating in the blood, but recent studies have shown that meningitis-causing pathogens are able to cross the blood-brain barrier as live organisms. We have developed the in vitro blood-brain barrier model by isolation and cultivation of human brain microvascular endothelial cells (HBMEC). Upon cultivation on collagen-coated Transwell inserts the HBMEC monolayers exhibit morphological and functional properties of tight junction formation and polar monolayer. Our Preliminary Studies revealed that meningitis-causing pathogens traverse the HBMEC monolayers without affecting the HBMEC integrity, as assessed by transendothelial electrical resistance and permeability, and microbial traversal of the HBMEC monolayers involves specific host signal transduction pathways. Our additional Preliminary Studies using pharmacological inhibition and gene deletion suggest for the first time that host 5-lipoxygenase is likely to be involved in microbial traversal of the blood-brain barrier. Leukotrienes are synthesized by 5-lipoxygenase and shown to have pathophysiological roles in respiratory diseases, allergic diseases and cardiovascular diseases, but their role in microbial traversal of the blood-brain barrier has not been explored. Our Preliminary Studies with the receptor antagonists revealed that cysteinyl leukotrienes are likely to be involved in microbial traversal of the blood-brain barrier. The overall aim of this application is to investigate and characterize the host signaling molecules involved in microbial traversal of the blood- brain barrier. The information derived from this application will demonstrate the novel contributions of 5- lipoxygenase and leukotrienes to microbial traversal of the blood-brain barrier.

Public Health Relevance

Microbial traversal of the blood-brain barrier is required for the development of central nervous system infection, but the underlying mechanisms remain incompletely understood. We propose to determine the contribution of the host molecules involving leukotrienes to microbial traversal of the blood-brain barrier.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI084984-05
Application #
8640878
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2010-05-15
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Zhu, Longkun; Maruvada, Ravi; Sapirstein, Adam et al. (2016) Cysteinyl leukotrienes as novel host factors facilitating Cryptococcus neoformans penetration into the brain. Cell Microbiol :
Kim, Kwang Sik (2016) Human Meningitis-Associated Escherichia coli. EcoSal Plus 7:
Wang, Ming-Hsien; Kim, Kwang Sik (2013) Cytotoxic necrotizing factor 1 contributes to Escherichia coli meningitis. Toxins (Basel) 5:2270-80
Thomsen, L B; Linemann, T; Pondman, K M et al. (2013) Uptake and transport of superparamagnetic iron oxide nanoparticles through human brain capillary endothelial cells. ACS Chem Neurosci 4:1352-60
Eigenmann, Daniela E; Xue, Gongda; Kim, Kwang S et al. (2013) Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood-brain barrier model for drug permeability studies. Fluids Barriers CNS 10:33
Yu, Hao; Kim, Kwang Sik (2012) mRNA context dependent regulation of cytotoxic necrotizing factor 1 translation by GidA, a tRNA modification enzyme in Escherichia coli. Gene 491:116-22
Maruvada, Ravi; Zhu, Longkun; Pearce, Donna et al. (2012) Cryptococcus neoformans phospholipase B1 activates host cell Rac1 for traversal across the blood-brain barrier. Cell Microbiol 14:1544-53
Kim, Kwang S (2012) Current concepts on the pathogenesis of Escherichia coli meningitis: implications for therapy and prevention. Curr Opin Infect Dis 25:273-8
Slanina, H; Schmutzler, M; Christodoulides, M et al. (2012) Effective plasmid DNA and small interfering RNA delivery to diseased human brain microvascular endothelial cells. J Mol Microbiol Biotechnol 22:245-57
Maruvada, Ravi; Kim, Kwang Sik (2012) IbeA and OmpA of Escherichia coli K1 exploit Rac1 activation for invasion of human brain microvascular endothelial cells. Infect Immun 80:2035-41

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