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Updated: May 20, 2026
Humanized Mouse Model to Study Bacterial Infections Targeting the Microvasculature
Published on: April 1, 2014
Identification of a novel pneumococcal vaccine antigen preferentially expressed during meningitis in mice
Layla K Mahdi1, Hui Wang, Mark B Van der Hoek
1Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
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 H(2)O(2). 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.
Insights
Streptococcus pneumoniae causes bacterial meningitis. Researchers identified alpha-glycerophosphate oxidase (GlpO) as a key virulence factor that aids bacterial invasion and causes cell damage, offering a potential target for new meningitis vaccines.
Area of Science:
- Microbiology
- Immunology
- Neuroscience
Background:
- Streptococcus pneumoniae is a leading cause of bacterial meningitis.
- Identifying pneumococcal virulence factors during meningitis is crucial for developing effective treatments and vaccines.
Purpose of the Study:
- To identify pneumococcal genes preferentially expressed during meningitis.
- To investigate the role of alpha-glycerophosphate oxidase (GlpO) in pneumococcal meningitis pathogenesis.
Main Methods:
- Genome-wide in vivo transcriptomic analysis in a mouse model of meningitis.
- In vitro adherence assays with human brain microvascular endothelial cells (HBMECs).
- Assessment of GlpO deletion mutant's virulence, immune response, and protective efficacy of GlpO-based immunization.
Main Results:
- Transcriptomic analysis revealed 34 altered bacterial genes in brain tissue, with 10 upregulated in both serotypes.
- A previously uncharacterized protein, GlpO, was identified as cytotoxic to HBMECs via H2O2 generation.
- glpO deletion mutants showed impaired adherence, reduced brain invasion, and attenuated inflammation, despite similar bacteremia levels.
- GlpO immunization conferred protection against invasive pneumococcal disease, enhanced by co-formulation with pneumolysin toxoid.
Conclusions:
- GlpO is a significant pneumococcal virulence factor contributing to meningitis development.
- Targeting GlpO represents a promising strategy for developing novel vaccines against invasive pneumococcal disease.
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