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dc.contributor.advisorButler, James
dc.contributor.advisorNagel, Zachary
dc.contributor.advisorShore, Stephanie
dc.contributor.advisorBi, Dapeng
dc.contributor.authorRhodes, Christalyn
dc.date.accessioned2019-08-08T13:14:18Z
dash.embargo.terms2020-05-01
dc.date.created2018-05
dc.date.issued2018-05-11
dc.date.submitted2018
dc.identifier.citationRhodes, Christalyn. 2018. Unjamming the Airway Epithelium: A Novel Role for Rhinovirus in Asthma Pathogenesis. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41129150*
dc.description.abstractHuman rhinoviruses are the leading causes of the common cold, known triggers of asthmatic exacerbations, and are also associated with the development of asthma. Despite many epidemiology studies establishing clear associations between rhinovirus infection and asthma development, the mechanism underlying this relationship has not been elucidated. Evidence suggests that early changes in bronchial epithelial cells play a crucial role in the development of the remodeled asthmatic airway. Physiologically, as normal epithelial layers develop, the cells collectively transition to a quiescent state, characterized by polygonal shaped cells that are caged by their neighbors and therefore immobile; a jammed state. While epithelial cells have the potential to collectively migrate, they have previously been shown to do so only as a feature of tissue level remodeling events that underlie wound repair, cancer metastases or embryogenesis. However, in response to broncho-constriction mimicking compressive stress, the mature epithelial layer unjams in a process which includes collective migration and changes in both the epithelial monolayer geometry and the distribution of cell shapes within that layer. The human bronchial epithelial cell (HBEC) layer from asthmatic donors studied in air liquid interface culture displays both a delayed transition to the jammed state during layer maturation as well as, following this, a prolonged unjammed state following compressive stress. Nevertheless, while delayed onset of the jamming transition has been shown to be a clear feature of cells from asthmatic donors, no known asthmatic triggers have been previously associated with airway epithelial unjamming. Here, I demonstrate that for cells that are in the mature, jammed state, when infected with human rhinovirus A (RVA), revert back to a fluid-like, migratory unjammed state that has been associated with cells from asthmatic donors. I further show that RVA infection-mediated unjamming can be attenuated by blocking RVA entry with an ICAM-1 receptor inhibitor. I further show that blocking TGFb signaling attenuates the migratory velocities in the induced unjammed phenotype promoted by viral infection. Our findings introduce, for the first time, viral infection as a potential mechanism by which the phenotype of normal (jammed) epithelial cells transitions to asthmatic-like (unjammed) epithelial cells as a result of rhinovirus A infection.
dc.description.sponsorshipBiological Sciences in Public Health
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectAsthma
dc.subjectrhinovirus
dc.subjectTGBb
dc.subjectjamming
dc.subjectunjamming transition
dc.subjectcollective migration
dc.subjectairway epithelium
dc.subjectICAM-1
dc.titleUnjamming the Airway Epithelium: A Novel Role for Rhinovirus in Asthma Pathogenesis
dc.typeThesis or Dissertation
dash.depositing.authorRhodes, Christalyn
dash.embargo.until2020-05-01
dc.date.available2019-08-08T13:14:18Z
thesis.degree.date2018
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
thesis.degree.nameDoctor of Philosophy
dc.type.materialtext
thesis.degree.departmentBiological Sciences in Public Health
thesis.degree.departmentBiological Sciences in Public Health
dash.identifier.vireo
dash.author.emailchristalyn.sims@yahoo.com


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