The interface between metabolism and virulence in environmental pathogens

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Environmental pathogens are microorganisms that live outside the human host but can gain access to the human body and cause disease. A remarkable example is the Burkholderia cepacia complex (Bcc), a group of Gram negative bacteria characterized by versatile catabolism, the ability to colonize diverse environments and associate with several hosts, including humans with the genetic disease cystic fibrosis (CF). In my previous NSERC Discovery program, I established a novel association between amino acid consumption and bacterial virulence. I discovered that an intermediate of phenylalanine catabolism, phenylacetic acid (PAA), modulates the Bcc quorum sensing (QS) response, which in turn regulates virulence. This NSERC research program will expand on amino acid catabolism during infection conditions with a focus on the biological significance of PAA-mediated regulation of QS.******My laboratory will use molecular biology tools and structural analysis to investigate whether PAA and other phenylalanine catabolism intermediates bind to quorum sensing regulators, and whether the identified interactions change their regulatory effect on virulence genes. B. cenocepacia, one of the species of the Bcc, can grow in the microoxic, amino acid-rich mucus of the CF lung and establish a chronic infection. To address the biological significance of PAA-related downregulation of virulence, we will investigate the contribution of phenylalanine degradation to QS-mediated pathogenicity in low oxygen conditions, where PAA degradation in Bcc may be abolished. B. cenocepacia is able to cause infection in the plant model Arabidopsis thaliana, allowing exploration of phenylalanine and PAA metabolism during a plant-bacteria interaction. PAA is a phytohormone and may be downregulated in plants as part of their defense mechanisms. To explore if B. cenocepacia can produce PAA-like molecules that enhance plant susceptibility to infection, we will use the A. thaliana host model and monitor disease progression in plants infected with B. cenocepacia mutants blocked at various stages of the PAA catabolism.******This research will establish the molecular basis of QS regulation by PAA catabolism, elucidating a novel link between two conserved bacterial features. The diverse pathogenic interactions of Bcc allow the use of plant and animal models. Thus, our findings will have broad implications for microbial metabolism during animal, human and plant-related microbial interactions. The cross-feeding between functional genomics, chemistry, and molecular biology will provide several training opportunities for interdisciplinary research, which is in high demand in the industry and academic sectors. Identification of the molecular mechanisms that connect the use of nutrients with QS will expose the intervening components as possible targets for therapeutic or biotechnological interventions. ***********