Regulatory Mechanisms in Bacterial Pathogens
Work in the area of regulatory mechanisms in bacterial pathogens is focused on understanding mechanisms utilized for bacterial colonization, and in particular in the ability of in vivo environmental factors to modulate bacterial gene expression. Transcriptional regulatory mechanisms have been defined on a global level in the pathogenic Neisseria species. We have established that the expression of virulence factors in these organisms is controlled by a global regulatory protein (ferric uptake regulator protein, Fur). We established that the gonococcal Fur protein functions as a global regulatory protein to either repress or activate expression (directly or indirectly) of a large repertoire of genes involved in a diverse set of metabolic and pathogenic pathways including anaerobic growth, antimicrobial resistance, and oxidative stress. We also demonstrated that several of these Fur-controlled genes coded for additional regulatory proteins, thus potentially expanding the Fur regulon via control of additional DNA-binding proteins. Figure: Fur interacts with other gonococcal regulatory proteins.
In addition to our in vitro studies we have also conducted studies to examine the expression of a subset of N. gonorrhoeae genes during in vivo mucosal infection in male and female patients attending a STD clinic in Boston MA. More recently we expanded these studies by partnering with our collaborators at the National Center for STD Control (NCSTD) in Nanjing, China. The NCSTD clinic is currently obtaining urethral specimens from males who report with gonococcal symptoms and vaginal lavage specimens from their matched female partners. These patients have enabled us to define N. gonorrhoeae gene expression profiles early during natural mucosal infection. For these studies we utilized RNA seq analysis to define the global transcriptome of N. gonorrhoeae during in vivo infection. Our analysis revealed a unique signature of gonococcal stress response, metabolism, and respiratory genes expressed during in vivo infection. Figure: Categorization of Gonococcal Genes Differentially Expressed During Infection Relative to Growth In Vitro A) increased expression, B) decreased expression.