UVM Theses and Dissertations
Format:
Print
Author:
LaBauve, Annette Estelle
Dept./Program:
Microbiology and Molecular Genetics
Year:
2014
Degree:
PhD
Abstract:
P. aeruginosa is a common free-living environmental bacterium that is also a successful opportunistic pathogen causing a wide array of both acute and chronic infections. Opportunistic infections of the lung are particularly devastating, representing the majority of morbidity and mortality associated with infection by P. aeruginosa. The tremendous metabolic versatility of P. aeruginosa aids in its success as a lung pathogen. The large genome of P. aeruginosa harbors a high proportion of regulatory genes that mediate diverse functions and enable sensing of host molecules-important in the context of opportunistic infection. The intrinsic versatility and ability to easily acquire antibiotic resistance mechanisms make P., aeruginosa a difficult pathogen to eradicate.
Understanding mechanisms and pathways P. aeruginosa employs to detect host environmental cues, establish an infection and thrive in the lung may illuminate novel treatment strategies that could relieve the burden remaining after current treatments and antibiotics, which are largely ineffective against this increasingly antibiotic resistant bacterium.
One such important response is through the action of transcriptional regulators which can provide means to sense the surrounding environment. AraC family transcriptional regulators have been shown to be involved in the regulation of carbon catabolism, stress response and virulence, often inducing transcription in response to molecules presentat the site of infection. Pulmonary surfactant was used as a model to investigate the early response of P. aeruginosa to the lung environment.
This dissertation presents two projects revolved around AraC family transcriptional regulators that respond to host-derived lipids to coordinate induction of virulence determinants. A previously unchar~cterized AraC family transcription factor that induced transcription of five genes in response to the sphingosine component of surfactant was characterized, and found to be important for survival in a murine model of acute pneumonia. Another previously characterized AraC family transcription fador, GbdR, was found to regulate a gene encoding a protein wIth hydrolase activity, choE, that may have a role in the extracellular secretion of the phosphatidylcholine-degrading virulence factor PlcH.
Understanding mechanisms and pathways P. aeruginosa employs to detect host environmental cues, establish an infection and thrive in the lung may illuminate novel treatment strategies that could relieve the burden remaining after current treatments and antibiotics, which are largely ineffective against this increasingly antibiotic resistant bacterium.
One such important response is through the action of transcriptional regulators which can provide means to sense the surrounding environment. AraC family transcriptional regulators have been shown to be involved in the regulation of carbon catabolism, stress response and virulence, often inducing transcription in response to molecules presentat the site of infection. Pulmonary surfactant was used as a model to investigate the early response of P. aeruginosa to the lung environment.
This dissertation presents two projects revolved around AraC family transcriptional regulators that respond to host-derived lipids to coordinate induction of virulence determinants. A previously unchar~cterized AraC family transcription factor that induced transcription of five genes in response to the sphingosine component of surfactant was characterized, and found to be important for survival in a murine model of acute pneumonia. Another previously characterized AraC family transcription fador, GbdR, was found to regulate a gene encoding a protein wIth hydrolase activity, choE, that may have a role in the extracellular secretion of the phosphatidylcholine-degrading virulence factor PlcH.