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dc.contributor.advisorRibera, Angeles
dc.contributor.advisorTyler, Kenneth L.
dc.contributor.authorHixon, Alison
dc.contributor.committeememberPerson, Abigail
dc.contributor.committeememberBennett, Jeffrey
dc.contributor.committeememberBarton, David
dc.contributor.committeememberBeckham, David
dc.date.accessioned2019-11-21T16:05:31Z
dc.date.available2020-09-25T16:05:40Z
dc.date.submitted2019
dc.descriptionIncludes bibliographical references.
dc.descriptionSummer
dc.description.abstractIn an effort to understand the paralytic disease caused by enterovirus D68 (EV-D68), we have developed a novel neonatal mouse model of infection that recapitulates many of the features of EV-D68-associated acute flaccid myelitis (AFM) (Chapter II). We found that several contemporary (circa 2014) strains of EV-D68 have the capacity to specifically infect and kill motor neurons in mice, resulting in the development of permanent paralysis. Older strains of EV-D68 did not cause disease in our model, suggesting that the recently observed changes in the EV-D68 genome may have facilitated both the respiratory and central nervous system (CNS) disease outbreaks. Furthermore, we used this model to effectively screen therapeutic drugs that would otherwise be difficult to systematically test in a human population (Chapter III). From these studies we identified that neutralizing antibodies to EV-D68 have the potential to reduce disease burden, while identifying two putative drug treatments – fluoxetine and intravenous corticosteroids – that should be avoided. Finally, we sought to understand the underlying mechanisms by which EV-D68 invades the spinal cord in order to kill the motor neurons (Chapter IV). To do this we developed an in vitro model using human induced pluripotent stem cell (hiPSC) motor neurons in a microfluidic culture system. From these studies, we conclude that EV-D68 can enter the CNS and spread via retrograde, but not anterograde, axonal transport. Importantly, we found that neither of the known EV-D68 receptors, sialic acid or intracellular adhesion molecule 5 (ICAM-5), play a role in infection of the motor neurons by circulating strains associated with AFM. Understanding this fundamental EV-D68 biology at the level of the motor neuron may eventually allow for the development of better treatment or prevention strategies.
dc.identifierHixon_ucdenveramc_1639D_10650.pdf
dc.identifier.urihttps://hdl.handle.net/10968/4581
dc.languageEnglish
dc.publisherUniversity of Colorado at Denver, Anschutz Medical Campus. Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 09/25/2020
dc.subjectAcute Flaccid Myelitis
dc.subjectNeurovirology
dc.subject.meshModels, Animal
dc.subject.meshMotor Neurons
dc.subject.meshMyelitis
dc.subject.meshEnterovirus D, Human
dc.titleFrom models to mechanisms : the pathogenesis and treatment of enterovirus D68-induced acute flaccid myelitis
dc.typeThesis
dcterms.embargo.expires2020-09-25
thesis.degree.disciplineNeuroscience
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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