Comparative genomics of Staphylococcus aureus: Implications for virulence and biofilm formation.

摘要

Staphylococcus aureus is a Gram-positive pathogen capable of causing a wide spectrum of disease, ranging from self-limited cutaneous infections to life-threatening infections such as sepsis, endocarditis, and musculoskeletal disease. Central to the pathogenicity of this organism is the ability to produce a diverse array of virulence factors, including surface factors which mediate adherence to host tissues, and secreted factors which mediate tissue destruction, spreading, and nutrient acquisition. Production of staphylococcal virulence factors is under complex regulatory control. In light of the increasing ability of Staphylococcus aureus to resist currently-available antimicrobial therapy, much research has focused on identification of novel therapeutic targets, including the regulatory factors that govern expression of virulence factors. However, much of our current understanding of staphylococcal pathogenesis is based on study of a limited number of laboratory strains. Previous studies have shown that these lab strains are not necessarily representative of clinical isolates, and that they often harbor regulatory mutations that affect overall patterns of gene expression. The work presented in this dissertation attempts to delineate the differences in clinical isolates of Staphylococcus aureus versus the well-characterized laboratory strains on a whole-genome scale. To this end, representative clinical isolates were compared to a prototypic laboratory strain to assess both differential genome content, and the differential expression of conserved genes. These experiments revealed that the regulatory networks defined in prototypic lab strains are not representative of predominant clinical isolates of Staphylococcus aureus. Furthermore, additional transcriptional profiling experiments allowed for redefinition of the target genes of the two most well-characterized staphylococcal global regulatory factors, agr and sarA, in a clinical strain. This approach led to the identification of a novel sarA-regulated locus, alsSD, which is essential for wild-type levels of biofilm formation in vitro and in vivo.