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 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.

Dynamic Changes in the Streptococcus pneumoniae Transcriptome during Transition from Biofilm Formation to Invasive Disease upon Influenza A Virus Infection

“…Some of the changes in expression of metabolic genes may be associated with an upregulation of the catabolite control protein A (ccpA) gene, which has been shown to induce glycolysis as well as expression of the ATP-binding protein MsmK (55), which regulates the 2-oxoacid dehydrogenase complex, lactate oxidase, and malA. The IAV-dispersed cells also upregulated glpO (␣-glycerophosphate oxidase), which was recently shown to act as a virulence factor during meningitis (56). Genes encoding neuraminidases A and B (nanA and nanB), enzymes involved in production of UDP-sugars and glycerolipid metabolism, were among the most highly upregulated genes observed (428-and 924-fold, respectively).…”

“…As an example, glpO was upregulated 60-fold and 509-fold in IAV-dispersed cells compared to biofilm and 37°C planktonic cells, respectively. glpO encodes a surface-expressed ␣-glycerophosphate oxidase involved in glycerol metabolism and was recently identified as a promising vaccine antigen in a screen for S. pneumoniae genes expressed during meningitis (56). Glycerol is more abundant than glucose in the brain, whereas glucose is more abundant in the blood (70,71).…”

Site of Isolation Determines Biofilm Formation and Virulence Phenotypes of Streptococcus pneumoniae Serotype 3 Clinical Isolates

“…pneumoniae is a diverse and adaptable pathogen, capable of surviving in a range of niches within its human host. Previous studies from our laboratory have identified changes in in vivo transcriptional profile within a given strain that facilitate survival in distinct host niches (nasopharynx, lungs, blood, and brain) and/or aid progression from one niche to another (26,27,35,36). However, genetic differences between strains also result in pneumococci with inherent tropism for one niche over another.…”

Directed vaccination against pneumococcal disease

“…1C). Specifically, vaccine candidates (i.e., antigens) were discovered by building on the fundamental insight that S. pneumoniae colonizes the nasopharynx as a biofilm and that disease progression occurs when external triggers resulting from changes in the nasopharyngeal environment prompt escape from the asymptomatic biofilm of bacteria with a changed transcriptional profile associated with increased virulence (22,23,34). Although current vaccines have provided protection and expanded coverage over time (Fig.…”