Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/72596
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Type: Journal article
Title: Identification of a novel pneumococcal vaccine antigen preferentially expressed during meningitis in mice
Author: Mahdi, L.
Wang, H.
Van der Hoek, M.
Paton, J.
Ogunniyi, A.
Citation: Journal of Clinical Investigation, 2012; 122(6):2208-2220
Publisher: Amer Soc Clinical Investigation Inc
Issue Date: 2012
ISSN: 0021-9738
1558-8238
Statement of
Responsibility: 
Layla K. Mahdi, Hui Wang, Mark B. Van der Hoek, James C. Paton and Abiodun D. Ogunniyi
Abstract: Streptococcus pneumoniae is the most common cause of severe bacterial meningitis in children, the elderly, and immunocompromised individuals. To identify virulence factors preferentially expressed during meningitis, we conducted niche-specific genome-wide in vivo transcriptomic analysis after intranasal infection of mice with serotype 4 or 6A pneumococci. The expression of 34 bacterial genes was substantially altered in brain tissue of mice infected with either of the 2 strains. Ten upregulated genes were common to both strains, 7 of which were evaluated for their role in the development of meningitis. One previously uncharacterized protein, a-glycerophosphate oxidase (GlpO), was cytotoxic for human brain microvascular endothelial cells (HBMECs) via generation of H2O2. A glpO deletion mutant was defective in adherence to HBMECs in vitro as well as in progression from the blood to the brain in vivo. Mutant bacteria also induced markedly reduced meningeal inflammation and brain pathology compared with wild type, despite similar levels of bacteremia. Immunization of mice with GlpO protected against invasive pneumococcal disease and provided additive protection when formulated with pneumolysin toxoid. Our results provide the basis of a strategy that can be adapted to identify genes that contribute to the development of meningitis caused by other pathogens.
Keywords: Cells, Cultured; Animals; Humans; Mice; Streptococcus pneumoniae; Meningitis, Pneumococcal; Glycerolphosphate Dehydrogenase; Bacterial Proteins; Streptolysins; Pneumococcal Vaccines; Toxoids; Antigens, Bacterial; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Mutation; Female
Rights: Copyright © 2012, American Society for Clinical Investigation
RMID: 0020119473
DOI: 10.1172/JCI45850
Appears in Collections:Molecular and Biomedical Science publications

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