Although prokaryotes have been extensively studied over the years, recent data have demonstrated that there are unexpected levels of complexity controlling gene expression in response to and adapting to changing environmental conditions. Quorum sensing is one regulatory system that has been identified in a number of Gram-negative bacteria.  This is a cell density-dependent system for regulating gene expression.  The basis of the system is that autoinducing signal molecules, such as acyl-homoserine lactones (AHLs) and PQS, are produced during bacterial growth. The concentration of these signal molecules increases with cell density and once a threshold concentration is reached, these molecules facilitate in activating expression of several target genes.  These signal mediated regulatory systems control the expression of a host of secondary metabolites and pathogenicity and virulence traits, including biofilm formation, in a number of pathogenic bacteria. Furthermore, to establish successful colonisation of biological niches, bacteria need to coordinate the expression of stress response and virulence factors, since the environment in host cells is stressful for bacteria. Several global regulatory networks are involved in co-ordinating this response including two component Sensor / Regulator and Post-transcriptional regulatory systems.

In the BRC, the importance of signalling in regulating host-microbe interactions using the bacteria Pseudomonas aeruginosa and Pseudomonas fluorescens, which interact with humans and plants respectively, and the interactive processes that take place during infections of lung epithelial cells by P. aeruginosa are main areas of research interest. Functional Genomics, based on Genechip technology, and Proteomics, are being developed and exploited to provide new approaches for the identification of complete sets of genes and proteins involved in particular functions including quorum sensing, secondary metabolite regulation, membrane fluidity and signal-mediated responses (Fig. 2).

Functional Genomics (Fig 2)

One novel regulatory system that has been described in Pseudomonas species is post-transcriptional control mediated by the RsmA protein and its cognate regulatory RNAs, RsmZ  & RsmY.  RsmA is a global post-transcriptional regulator that modulates the translation of a number of mRNAs encoding proteins involved in secondary metabolite production and virulence.  RsmA can be sequestered by the RsmZ/Y RNAs, which relieves the translational regulation. The RsmA/RsmZ/Y system is under the control of environmentally responsive two component regulators including GacA/GacS. Thus, there is a complex post-transcriptional regulatory network controlling expression of secondary metabolites and virulence.  Part of our research in this area involves characterising this network in Pseudomonas species.  Recent data links quorum sensing signalling and RsmA pathways with membrane integrity, type three secretion of effector toxins and antibiotic resistance, creating an exciting research theme exploring the interactions between these pathways.

More recently, this research has extended to investigating regulatory networks involved in membrane composition and the bacterial response to stressful environments. There is evidence to indicate that activation of stress responses during lung infections favours the persistence of this bacterium in the host’s environment. Our interest is to understand the correlation between bacterial pathogenesis and stress response pathways, using P. aeruginosa as a model organism.

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