Genome dynamics in the evolution of virulence in gram positive commensals
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Common genetic processes drive the evolution of both pathogens and commensals in response to selective environmental pressures. Thus, instances where two related species in a common environmental niche evolve towards divergent lifestyles (one as a pathogen and the other as a commensal) are especially significant to understanding the evolution of bacterial virulence. Members of the genera Staphylococcus and Streptococcus exist as commensal flora in the human body, but are also associated with severe nosocomial infections. This dissertation aims to elucidate the roles of recombination and lateral gene transfer in the evolution of virulence in two commensal members of these genera, Staphylococcus epidermidis and Streptococcus gordonii. S.epidermidis is used to study the effects of lateral gene transfer, while the naturally competent S.gordonii, a colonizer of the oral cavity, makes an interesting model to analyze the effects of DNA uptake and homologous recombination events. S.epidermidis is associated with nosocomial, prosthetic valve endocarditis, but does not cause the wide variety of other severe infections associated with its more virulent relative S.aureus. In the first part of this research (Aim 1), we characterize an enterotoxin-bearing pathogenicity island identified in the clinical isolate S.epidermidis FRI909, and address two questions about lateral gene transfer: (i) Do laterally transferred pathogenicity islands in commensal host genomes retain the same characteristics they have in their more virulent donors? (ii) Do some genomic factors make certain species more likely to acquire virulence genes than others? The second half of this project (Aim 2) examines the effects of DNA uptake and homologous recombination in the naturally competent commensal species, S.gordonii. Eight clinical oral isolates of S.gordonii were studied for differences in endocarditis-associated phenotypes in a previous study. Using these strains, we ask the question- Can random, neutral recombination, independent of any apparent selective pressure; result in convergent evolution of clinical strains towards a common phenotype? The hitchhiking effects of recombination (which occur downstream of a gene that is under selective pressure) can influence unrelated genes profoundly. One such gene downstream of a penicillin-binding protein that is under antibiotic selective forces is the D-alanyl-D-alanine ligase ( ddl ) gene, which is the subject of further studies in Aim 3. The latter part of this work (Aim 3) elucidates the contribution of the ddl gene to innate immune resistance in these strains. Earlier believed to be a housekeeping gene involved in peptidoglycan synthesis, ddl is now known to be susceptible to selective pressure and recombination. Our studies of ddl expression and function elucidate the idea that positive selective pressure on a gene (here, pbp1b ) can influence unrelated, downstream genes, resulting in pleiotropic effects on immune evasion and consequently, virulence. Overall, the work proposed in this dissertation attempts to understand the effects of two mechanisms of genome adaptation, recombination and lateral gene transfer, on the evolution of pathogenicity in common members of the human microflora. We address the the contribution of overall genome diversity and recombination events towards paradigm shifts in bacterial lifestyles. Our results are likely to contribute significantly to our understanding of the driving forces behind bacterial genome evolution, and how these forces influence human health and disease.