Our laboratory has several ongoing projects including:
1. Cell envelope stress (CES) and the response to human antimicrobial peptides in group A Streptococcus (GAS). Using a combination of clinical bacterial strain surveillance and whole genome sequencing we discovered variation in a highly conserved gene regulatory system among Gram-positive pathogens, LiaFSR, that led to persistence of GAS in humans. Subsequently, our investigative studies have shown that LiaFSR is intimately involved in the response to CES induced by host antimicrobial peptides. Currently, studies are focused on the role of the membrane proteins LiaF and LiaS in sensing CES through the GAS functional membrane microdomain, the ExPortal. In addition, we are interested in the downstream gene regulatory effects mediated by LiaR following activation by LiaS. Our research in this area is supported by an NIH R01.
2. Emm4 GAS clonal emergence in North America. Through local and national-level clinical GAS strain surveillance and comprehensive bacterial strain whole genome sequencing (WGS) we discovered a near complete clonal replacement of emm4 GAS strains over a 20-year period in the United States and Canada. Extensive phylogenomic, transcriptomic, and phenotypic analyses indicate that, in contrast to previous reports of GAS clonal emergence associated with large-scale recombination, emergent emm4 GAS strain pathogenesis is attributable to a small number of small genetic changes (mutations). In collaboration with the laboratory of Samuel Shelburne, MD, PhD (MD Anderson Cancer Center), our laboratory is investigating the mechanism(s) by which emergent emm4 GAS display enhanced fitness in humans. Efforts in this area are supported by an NIH R21.
3. Evolution and pathogenesis of serotype V group B Streptococcus (GBS) in humans. In contrast to the extensive research performed in early infant disease caused by GBS, very few efforts have been made to understand the mechanisms contributing to expanding GBS disease in non-pregnant adults. Furthermore, in contrast to the predominance of serotype III GBS strains in infants, adult disease strains are most commonly serotype V. Our laboratory has performed some of the only studies to understand the epidemiology and pathogenesis of serotype V GBS disease in adults. Similar to our studies in emm4 GAS, using local GBS surveillance spanning 50 years, WGS, and phylogenomic analysis, we have discovered stepwise emergence of multiple serotype V subpopulations differing by inactivation of a conserved gene regulatory system (TCS3). Ongoing studies are aimed at determining the role of TCS3 in GBS pathogenesis and subpopulation emergence and we were recently awarded an NIH R21 to support our endeavors.
4. Clinical disease strain surveillance in GAS and GBS. In addition to mechanistic studies of clonal emergence, our laboratory leverages ongoing multicenter clinical disease strain surveillance to understand the emergence of antimicrobial resistance (AMR) and contribution of AMR to GAS and GBS pathogenesis. We are interested in the development of near real-time bacterial strain surveillance that merges clinical phenotypes (e.g. clinical disease type, antimicrobial resistance phenotype) with bacterial strain WGS data. Multiple projects in both GAS and GBS are currently underway in this arena.
Current interests in the lab include:
- Mechanisms of epidemic clone emergence in pathogenic streptococci.
- Gene regulatory networks of GAS/GBS.
- Epidemiology of antimicrobial resistance in GAS/GBS.
- Clinical epidemiology of GAS/GBS disease in humans.