Bacterial meningitis continues to be an important cause of mortality and morbidity, such as developmental delay, hearing loss and cognitive impairment. The Metropolitan Atlanta Developmental Disabilities Surveillance Program identified bacterial meningitis as the leading postnatal cause of developmental disabilities. A major contributing factor to such mortality and morbidity is our incomplete knowledge on the pathogenesis of this disease. E. coli is the most common Gram-negative bacillary organism causing meningitis. Several lines of evidence from human cases and experimental animal models of E. coli meningitis indicate that E. coli penetration into the brain follows a high level f bacteremia and cerebral capillaries are the portal of E. coli entry into the brain. Since E. coli entry into the brain occurred in the cerebral microvessels, we developed the blood-brain barrier model with human brain microvascular endothelial cells (HBMEC) to study E. coli penetration of the blood-brain barrier. Our HBMEC monolayer, upon cultivation on collagen-coated Transwells, exhibits spatial organization of tight and adherens junction proteins as well as a polarized monolayer, a unique property of the blood-brain barrier endothelial cells. We have shown for the first time that meningitis-causing E. coli strains exhibit the ability to invade the HBMEC monolayer and that the ability of HBMEC invasion is correlated with E. coli penetration into the brain in vivo. The underlying mechanisms involved in E. coli penetration of the blood-brain barrier, however, remain incompletely understood. These findings indicate that new approaches are needed to investigate E. coli penetration of the blood-brain barrier. We have used E. coli invasion of HBMEC monolayer as a biologically relevant new approach for discovery of targets affecting E. coli penetration of the blood-brain barrier. This application is to take advantage of the new targets identified from our chemical screen for investigating how they contribute to E. coli penetration of the blood-brain barrier in vitro and in vivo. Characterization of such targets will demonstrate a novel strategy exploited by meningitis-causing E. coli strains for penetration of the blood-brain barrier, the essential step in the development of E. coli meningitis.

Public Health Relevance

Bacterial meningitis is of considerable public health interest, and it is important to develop new information that will help in its prevention and therapy. This project aims to investigate the new mechanisms contributing to E. coli penetration of the blood-brain barrier, the essential step in the development of E. coli meningitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS091102-04
Application #
9502412
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2015-09-30
Project End
2020-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Miraglia, María C; Rodriguez, Ana M; Barrionuevo, Paula et al. (2018) Brucella abortus Traverses Brain Microvascular Endothelial Cells Using Infected Monocytes as a Trojan Horse. Front Cell Infect Microbiol 8:200
Zhao, Wei-Dong; Liu, Dong-Xin; Wei, Jia-Yi et al. (2018) Caspr1 is a host receptor for meningitis-causing Escherichia coli. Nat Commun 9:2296
Bramley, John C; Drummond, Coyne G; Lennemann, Nicholas J et al. (2017) A Three-Dimensional Cell Culture System To Model RNA Virus Infections at the Blood-Brain Barrier. mSphere 2:
Figueira, I; Garcia, G; Pimpão, R C et al. (2017) Polyphenols journey through blood-brain barrier towards neuronal protection. Sci Rep 7:11456
Lee, Seon-Bong; Kim, Ju-Hyeong; Cho, Myung-Haing et al. (2017) Impact of commercial cigarette smoke condensate on brain tissue co-cultured with astrocytes and blood-brain barrier endothelial cells. J Toxicol Environ Health A 80:533-541
Starost, Laura Julia; Karassek, Sascha; Sano, Yasuteru et al. (2016) Pertussis Toxin Exploits Host Cell Signaling Pathways Induced by Meningitis-Causing E. coli K1-RS218 and Enhances Adherence of Monocytic THP-1 Cells to Human Cerebral Endothelial Cells. Toxins (Basel) 8:
Wang, Xiangru; Maruvada, Ravi; Morris, Andrew J et al. (2016) Sphingosine 1-Phosphate Activation of EGFR As a Novel Target for Meningitic Escherichia coli Penetration of the Blood-Brain Barrier. PLoS Pathog 12:e1005926
Kim, Kwang Sik (2016) Human Meningitis-Associated Escherichia coli. EcoSal Plus 7: