Investigating the role of the phenylacetic acid pathway in the quorum sensing-regulated virulence of cystic fibrosis pathogens

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dc.contributor.supervisor Cardona, Silvia (Microbiology) en_US
dc.contributor.author Lightly, Tasia
dc.date.accessioned 2020-03-19T19:57:55Z
dc.date.available 2020-03-19T19:57:55Z
dc.date.copyright 2020-03-16
dc.date.issued 2020 en_US
dc.date.submitted 2020-03-17T01:11:11Z en_US
dc.identifier.citation Pribytkova, T., Lightly, T. J., Kumar, B., Bernier, S. P., Sorensen, J. L., Surette, M. G., & Cardona, S. T. (2014). The attenuated virulence of a Burkholderia cenocepacia paaABCDE mutant is due to inhibition of quorum sensing by release of phenylacetic acid. Molecular Microbiology, 94(3), 522–536. 32. https://doi.org/10.1111/mmi.12771 en_US
dc.identifier.citation Lightly, T. J., Phung, R. R., Sorensen, J. L., & Cardona, S. T. (2017). Synthetic cystic fibrosis sputum medium diminishes Burkholderia cenocepacia antifungal activity against Aspergillus fumigatus independently of phenylacetic acid production. Canadian Journal of Microbiology, 63(5), 1–12. 27. https://doi.org/10.1139/cjm-2016-0705 en_US
dc.identifier.citation Lightly, T. J., Frejuk, K. L., Groleau, M.-C., Chiarelli, L. R., Ras, C., Buroni, S., Déziel, E., Sorensen, J. L., & Cardona, S. T. (2019). Phenylacetyl-CoA, not phenylacetic acid, attenuates CepIR-regulated virulence in Burkholderia cenocepacia. Applied and Environmental Microbiology, 85:e01594-19. https://doi.org/10.1128/AEM.01594-19 en_US
dc.identifier.uri http://hdl.handle.net/1993/34577
dc.description.abstract For successful bacterial infection, bacteria need to sense and respond to their environment. Quorum sensing (QS) allows bacteria to regulate their virulence in a cell-density dependent manner. Polymicrobial infections are prevalent in cystic fibrosis (CF) infections but the interactions between these microbes are not well understood. The phenylacetic acid (PAA) pathway is upregulated in CF-like conditions and PAA was linked to the attenuation of virulence in two major CF pathogens, Burkholderia cenocepacia and Pseudomonas aeruginosa. However, the mechanism of attenuation remains unknown. The goals of my thesis were to investigate the role of PAA release in CF pathogen interactions, identify the PAA pathway metabolite responsible for the attenuation of virulence, and determine if the mechanism of inhibition is due to an effect on the CepIR QS system (either directly or indirectly). I investigated the accumulation of PAA in CF pathogens. I determined that B. cenocepacia was the most likely candidate for the accumulation of PAA but that PAA did not affect the pathogen interactions. I then characterized knockout mutants of the first steps of the PAA pathway (PaaK or PaaABCDE) to determine which PAA metabolite(s) are responsible for the attenuation of virulence. While loss of the paaABCDE operon resulted in decreased virulence, a paaK deficient strain had increased virulence compared to wild type despite the fact that both mutations resulted in higher levels of external PAA. Although we found no evidence of direct cepI or cepR downregulation by PAA or PAA-CoA, a low-virulence cepR mutant reverted to a virulent phenotype upon removal of the paaK genes. Whereas removal of the paaABCDE operon in the cepR mutant had no bearing on its attenuated phenotype. These results demonstrate that B. cenocepacia can elicit a pathogenic response if PAA-CoA is not produced. Conversely, the accumulation of PAA-CoA appears to attenuate pathogenicity. In summary, this thesis demonstrates that a metabolic signal can activate virulence in B. cenocepacia when the classical QS system is not functioning. This finding challenges the classical view of virulence activation by QS, providing new insight into the relationship between metabolism and virulence in opportunistic pathogens. en_US
dc.rights info:eu-repo/semantics/openAccess
dc.subject Phenylacetic acid en_US
dc.subject Quorum Sensing en_US
dc.subject Burkholderia cenocepacia en_US
dc.subject Cystic fibrosis en_US
dc.subject Phenylacetyl-CoA en_US
dc.subject Microbiology en_US
dc.subject Gram-negative en_US
dc.subject Pseudomonas aeruginosa en_US
dc.subject Aspergillus fumigatus en_US
dc.subject Metabolism en_US
dc.subject Virulence en_US
dc.title Investigating the role of the phenylacetic acid pathway in the quorum sensing-regulated virulence of cystic fibrosis pathogens en_US
dc.type doctoral thesis en_US
dc.type info:eu-repo/semantics/doctoralThesis
dc.degree.discipline Microbiology en_US
dc.contributor.examiningcommittee Brassinga, Karen (Microbiology) en_US
dc.contributor.examiningcommittee de Kievit, Teresa (Microbiology) en_US
dc.contributor.examiningcommittee Sorensen, John (Chemistry) en_US
dc.contributor.examiningcommittee Eberl, Leo (Plant and Microbial Biology, University of Zurich) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note May 2020 en_US

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