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Authors: Lorestani, Alexander
Advisors: Gitai, Zemer
Contributors: Molecular Biology Department
Subjects: Microbiology
Issue Date: 2017
Publisher: Princeton, NJ : Princeton University
Abstract: Mechanical cues are a ubiquitous feature of host-pathogen interactions. While the effect of physical forces on eukaryotic host cell biology is well-established, their role in regulating the behaviors of pathogenic bacteria is only emerging. Here I describe how Pseudomonas aeruginosa, a leading cause of healthcare-associated infections, senses and responds to forces generated by fluid flow. I develop a microfluidic model of P. aeruginosa infections, where surface-attached bacteria are exposed to tunable flow-generated forces. I use RNA-seq to discover an active transcriptional response to fluid flow and identify froABCD, a colonization determinant, as the first flow-regulated operon described in this pathogen. A froABCD transcriptional reporter serves as a surrogate for the global P. aeruginosa flow response and is regulated specifically by shear stress. Further, I discover that froABCD transcription is regulated by a previously uncharacterized sigma factor/anti-sigma factor pair, FroR/FroI. Validating the use of the froABCD as a flow reporter, we provide evidence that the entire P. aeruginosa flow response is regulated by FroI. Together, these data are the first evidence that a flow-generated force regulates gene expression in surface-attached P. aeruginosa. This work makes a fundamental contribution to the growing body of evidence that the hallmarks of bacterial pathogenesis are regulated by the integration of a diverse set of environmental cues, including physical forces.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog:
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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Lorestani_princeton_0181D_12236.pdf3.8 MBAdobe PDFView/Download
Lorestani_princeton_0181D_408/Supplementary Movie 2-1.avi118.82 MBUnknownView/Download
Lorestani_princeton_0181D_408/Supplementary Movie A3-1.avi171.43 MBUnknownView/Download
Lorestani_princeton_0181D_408/Supplementary Table 2-1 - WT PA14 0 and 4 hrs flow - full.xlsx2.91 MBMicrosoft Excel XMLView/Download
Lorestani_princeton_0181D_408/Supplementary Table 2-2 - WT PA14 0 and 4 hrs flow - threshold.xlsx255.82 kBMicrosoft Excel XMLView/Download
Lorestani_princeton_0181D_408/Supplementary Table 2-3 - WT PA14 0 to 90 min flow - full.xlsx4.86 MBMicrosoft Excel XMLView/Download
Lorestani_princeton_0181D_408/Supplementary Table 2-4 - WT vs froABCD 4 hrs flow.xlsx11.8 MBMicrosoft Excel XMLView/Download

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