“There are several things about the graduate program in the Department of Microbiology and Immunology that make me believe that it is the ideal environment for graduate studies. One striking aspect of Wake is the innovative thinking that drives the institution. Everything from the IBM ThinkPad program to the faculty and their research demonstrate that this is a place on the cutting edge. In addition, the smaller size of the program creates an environment where students can have direct access to the faculty members and all the resources that Wake has to offer. That said, I feel there was one factor that clearly separated this Microbiology and Immunology program from all the others. Quite simply I felt that Wake offered the best program to prepare me for the next step. In talking to the Microbiology faculty and other people associated with the institution it is quite obvious that they are completely dedicated to the students and their development as professionals.”
Srv and Group A streptococcal pathogenesis
Group A Streptococcus (GAS) causes a greater variety of human diseases than any other bacterial pathogen, yet little is understood about GAS gene regulation in vivo. Recently, the first GAS member of the Crp/Fnr family of transcriptional regulators was described. The gene, named srv for streptococcal regulator of virulence, encodes a 240 amino acid (aa) protein with 53% aa similarity to PrfA, a transcriptional activator of virulence in Listeria monocytogenes. An isogenic mutant strain of GAS lacking srv exhibited significantly attenuated virulence in a mouse model of GAS bacteremia. Furthermore, microarray analysis indicated that 21% (354/1678) of GAS genes are down regulated in vitro in the srv mutant strain. The overall goal of this project is to test the hypothesis that Srv is a critical transcriptional activator of factors that promote GAS survival in the host. In Aim 1, we will determine the mechanism by which Srv mediates transcription and delineate those genes directly influenced by Srv. Two complementary methods, an in vitro genomic evolution of ligands by exponential enrichment (SELEX), and an in vivo genomic binding site analysis will be used to identify target sequences bound by Srv. Aim 2 will seek to determine the effect of Srv-mediated gene regulation on GAS survival in vivo. We will study the ability of three GAS strains and their isogenic srv mutant derivatives to survive in a mouse soft-tissue model of GAS infection. Understanding the basic mechanisms of Srv gene regulation will provide insight into how GAS mediates interactions with the host and may lead to novel therapeutic approaches.