UC San Diego

We live in a world dominated by the microbes that have made their homes in and around us since the beginnings of human life. A major advancement in our understanding of the role microbes play in our lives came about in the recognition that many diseases are caused by microorganisms that have found ways to occupy our bodies. A still larger advancement was the realization that bacteria produce molecules that modulate host defenses in broad and targeted ways. Advances in our understanding of the host-pathogen relationship at the molecular level have relied on methods that evaluate one or a few molecules at a time. However, recent developments in unbiased -omics technologies are highly suited to studying the vast arsenal of molecules that bacteria use to subvert host defenses. This work describes one such -omics strategy for the discovery of novel bacterial virulence factors, termed Biomimetic Virulomics (BV). In chapter 1, I describe the impact of technological improvements in delineating the function of previously undescribed virulence factors on human health. I describe the results of a BV experiment oriented at discovering novel red blood cell-targeted virulence factors in the important human pathogen, Streptococcus pyogenes, also known as Group A Streptococcus (GAS). In chapter 2, I present an initial characterization of one of the GAS virulence factors discovered through this method, S protein, a previously-overlooked GAS virulence factor. In chapter 3, I expand on the initial description of S protein into the realm of vaccine development, finding that recombinant S protein is robustly protective against localized GAS skin infections. In chapter 4, I describe an S protein homolog in another important human pathogen and cause of neonatal morbidity, Group B Streptococcus (GBS). I find that as in GAS, GBS S protein is critical for bacterial pathogenesis. In chapter 5, I use quantitative proteomics paired with tissue-type specific isolation methods to describe the effect of another important GBS virulence factor, iagA, on manipulating the blood-brain barrier during meningitis. Finally, in chapter 6, I present the future plan and broader implications for the work encompassed in this thesis as a grant application.