Characterization of Pneumococcal Genes Involved in Bloodstream Invasion in a Mouse Model.

Layla K Mahdi,Esmaeil Ebrahimie,Mark B Van Der Hoek,James C Paton,Abiodun D Ogunniyi,Dennis W Metzger

doi:10.1371/journal.pone.0141816

Layla K Mahdi, Esmaeil Ebrahimie + Show 4 more

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https://doi.org/10.1371/journal.pone.0141816

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Journal: PloS one	Publication Date: Nov 5, 2015
Citations: 19	License type: CC BY 4.0

Affiliation: University of Adelaide, South Australia Pathology

Abstract

Streptococcus pneumoniae (the pneumococcus) continues to account for significant morbidity and mortality worldwide, causing life-threatening diseases such as pneumonia, bacteremia and meningitis, as well as less serious infections such as sinusitis, conjunctivitis and otitis media. Current polysaccharide vaccines are strictly serotype-specific and also drive the emergence of non-vaccine serotype strains. In this study, we used microarray analysis to compare gene expression patterns of either serotype 4 or serotype 6A pneumococci in the nasopharynx and blood of mice, as a model to identify genes involved in invasion of blood in the context of occult bacteremia in humans. In this manner, we identified 26 genes that were significantly up-regulated in the nasopharynx and 36 genes that were significantly up-regulated in the blood that were common to both strains. Gene Ontology classification revealed that transporter and DNA binding (transcription factor) activities constitute the significantly different molecular functional categories for genes up-regulated in the nasopharynx and blood. Targeted mutagenesis of selected genes from both niches and subsequent virulence and pathogenesis studies identified the manganese-dependent superoxide dismutase (SodA) as most likely to be essential for colonization, and the cell wall-associated serine protease (PrtA) as important for invasion of blood. This work extends our previous analyses and suggests that both PrtA and SodA warrant examination in future studies aimed at prevention and/or control of pneumococcal disease.

Highlights

Streptococcus pneumoniae is a formidable human pathogen, responsible for significant morbidity and mortality worldwide
The analyses were performed using existing transcriptomic data obtained from two S. pneumoniae strains, WCH16 and WCH43, after intranasal challenge of mice
In spite of the availability of antimicrobial therapy and conjugate vaccines, S. pneumoniae continues to be responsible for massive global morbidity and mortality

Summary

Introduction

Streptococcus pneumoniae (the pneumococcus) is a formidable human pathogen, responsible for significant morbidity and mortality worldwide It causes a broad spectrum of diseases ranging from less serious infections such as sinusitis, conjunctivitis and otitis media, to potentially fatal diseases such as pneumonia, bacteraemia and meningitis. Concerted global efforts are focused on accelerating the development of alternative pneumococcal vaccine strategies that address the shortcomings of existing approaches, without compromising efficacy. One such approach involves a detailed assessment of pneumococcal proteins that contribute to pathogenesis and are common to all serotypes, their development as vaccine antigens, and an understanding of the mechanism whereby protection might be elicited. The virulence proteins which have received the greatest attention and shown consistent promise as vaccine candidates to date include the thiol-activated toxin pneumolysin (Ply), two choline-binding surface proteins called pneumococcal surface protein A (PspA) and choline-binding protein A (CbpA) ( referred to as PspC or SpsA), iron uptake protein PiuA and various combinations thereof [4,5,6,7,8,9,10,11]

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