Identification of a novel pneumococcal vaccine antigen preferentially expressed during meningitis in mice
Layla K. Mahdi, … , James C. Paton, Abiodun D. Ogunniyi
Layla K. Mahdi, … , James C. Paton, Abiodun D. Ogunniyi
Published May 24, 2012
Citation Information: J Clin Invest. 2012;122(6):2208-2220. https://doi.org/10.1172/JCI45850.
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Research Article Infectious disease

Identification of a novel pneumococcal vaccine antigen preferentially expressed during meningitis in mice

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, α-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.

Authors

Layla K. Mahdi, Hui Wang, Mark B. Van der Hoek, James C. Paton, Abiodun D. Ogunniyi

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Figure 5

Pathological investigations of mice challenged with WCH43 and ΔglpO.

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Pathological investigations of mice challenged with WCH43 and ΔglpO. (...
(A) Neutrophil percentages determined from differential counts of leukocytes in Giemsa-stained mouse peripheral blood smears at 48 hours after i.n. challenge. Data represent mean ± SEM from 2 experiments. *P < 0.05; **P < 0.01, Student’s t test (relative to uninfected mice). (B). Macroscopic views of freshly removed mouse brains at 48 hours after i.n. challenge. demonstrating surface vessel dilations, in WCH43- and ΔglpO-challenged mice. (C) Microscopic views of H&E-stained mouse brain sections at 48 hours after challenge. The upper panels are from the mid-brain/cerebellum region, showing small vessel dilations, microhemorrhages, and microthrombi in the parenchyma (arrowheads) in WCH43-challenged mice. The middle panels are from the boundary between the mid-brain and cerebral cortex, showing meningeal inflammation, particularly in WCH43-challenged mice (arrowheads). Meningeal regions labeled a, b, and c are enlarged in the bottom panels. Scale bars are as indicated. Views presented are representative of 6 sections derived from 2 different mice for each challenge strain.