Simon Dove

Research Description

Successful infection of a host organism by a bacterial pathogen depends critically on its ability to make the appropriate virulence factors at the right time and place. This is achieved through the coordinate regulation of virulence genes, the expression of which is typically controlled at the level of transcription by proteins that modulate the activity of RNA polymerase (RNAP). Research in my laboratory focuses on the regulation of transcription in pathogenic bacteria with emphasis on regulators that contact RNAP, and regulators that control virulence gene expression.

Several current projects concern the regulation of virulence gene expression in Pseudomonas aeruginosa, an opportunistic pathogen that infects the lungs of cystic fibrosis (CF) patients. In the chronically infected CF lung the organism persists as a biofilm—a surface attached community of bacteria encased in a polymeric matrix. Prominent amongst those genes that play a role in biofilm formation in P. aeruginosaare the cupA genes, which encode components of a putative fimbrial structure that facilitates surface-attachment. We have found that MvaT and MvaU, which are members of the histone-like nucleoid structuring (H-NS) family of proteins, control the phase-variable (i.e. ON/OFF) expression of the cupA fimbrial gene cluster. Current work is aimed at determining how these proteins, whose function is essential in P. aeruginosa, exert their control on cupA and on the many other virulence genes they control. We are also trying to understand how a novel small RNA we have identified controls expression of the cupA gene cluster.

Although widespread among multicellular organisms, there are relatively few documented instances of programmed cell death (PCD) in bacteria. We have identified a PCD pathway in Pseudomonas aeruginosa that enhances the ability of the bacterium to cause disease in a lung infection model. Activation of the system can occur in a subset of cells in response to DNA damage through cleavage of an essential transcription regulator we call AlpR. Cleavage of AlpR triggers a cell lysis program through derepression of the alpA gene, which encodes a positive regulator that activates expression of the alpBCDE lysis cassette. While this is lethal to the individual cell in which it occurs, we find it benefits the population as a whole during infection of a mammalian host. We would like to understand how the Alp regulators mediate their effects, how certain Alp proteins mediate lysis of the bacterial cell, and to elucidate how a pathogen exploits PCD as a survival-promoting strategy during the course of an infection.

Other work in the laboratory involves the study of three transcription regulators from Francisella tularensis, the causative agent of tularemia, that are essential for the intramacrophage growth and survival of the organism. One of these regulators is a putative DNA-binding protein that functions through interaction with an RNAP-associated complex formed by the other two. We are interested in determining how these regulators function coordinately to control a common set of genes and how the activity of these regulators is influenced by a small molecule.