Phage-like Chromosomal Islands and Virulence in Pneumococci

$251,600P20FY2019GMNIH

Oklahoma State University Stillwater, Stillwater OK

Investigators

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Abstract

Project Summary Streptococcus pneumoniae is a major cause of human respiratory disease worldwide. 30% of severe cases are caused by strains that are fully resistant to one or more clinically relevant antibiotics. Previously, the PI has shown that phage-like chromosomal islands (CI) in group A streptococci cause the cell to 1) adopt a mutator phenotype through disruption of DNA repair, which promotes antibiotic resistance, and 2) alter global transcription by up-regulating virulence genes that can enhance pathogenicity, colonization, and antibiotic resistance. We have constructed strains of S. pneumoniae TIGR4 that differ by the presence or absence of a novel CI that has the potential to regulate nucleotide excision repair via site-specific integration. Preliminary studies show that such elements alter global transcription patterns, including genes that contribute to survival and/or biofilm formation. The central hypothesis of this proposal is that SpnCI acts as a molecular switch to control a mutator phenotype and shift global transcriptional patterns to increase virulence or promote survival. To test this hypothesis, the following specific aims will be performed: 1) Characterize the contribution of SpnCI site-specific integration to a mutator phenotype in a pneumococcal acute infection model, 2) Determine the impact of gene deletions within SpnCI on the transcriptome of S. pneumoniae in culture and in the wax worm model of pathogenesis, and 3) Identify the contribution of SpnCI to virulence in an acute in vivo infection model. This study will provide the first evidence of the biological impact of SpnCI in relevant infection models. The PI is highly qualified to perform these studies, having pioneered the discovery and characterization of these streptococcal CI. The proposed studies will have a positive impact, fundamentally advancing our understanding of the biology of this pathogen and may lead to new antimicrobial strategies and improved patient care.

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