Characterization of Host Factors Affecting Viral Entry

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dc.contributor.advisorAlto, Nealen
dc.contributor.committeeMemberSchoggins, John W.en
dc.contributor.committeeMemberPfeiffer, Julie K.en
dc.contributor.committeeMemberReese, Tiffany A.en
dc.creatorRinkenberger, Nicholas Ryanen
dc.creator.orcid0000-0002-5228-1727
dc.date.accessioned2021-06-03T22:33:25Z
dc.date.available2021-06-03T22:33:25Z
dc.date.created2019-05
dc.date.issued2019-04-10
dc.date.submittedMay 2019
dc.date.updated2021-06-03T22:33:25Z
dc.descriptionThe file named "RINKENBERGER-DISSERTATION-2019.pdf" is the primary dissertation file. Two (2) supplemental video files are also available and may be viewed individually.en
dc.description.abstractViruses are obligate, intracellular parasites. For a virus to infect a host cell, it must gain access to the interior of the host cell by some means. In animals, this often involves the exploitation of host processes such as receptor-mediated endocytosis and vesicular trafficking. Zika virus is an emerging arbovirus with global health and economic impacts. Interestingly, while Asian lineage Zika virus causes human disease and has been associated with severe neurological complications, African lineage Zika virus has only rarely been reported to cause human disease. Large strides have been made in understanding Zika virus infection. However, the mechanism used by Zika virus to enter host cells remains somewhat obscure. In chapter 2, I delineate and compare the pathway utilized by both Asian and African lineage Zika virus to enter host cells. I find that these viruses require clathrin-mediated endocytosis and Rab5a function in a conserved manner. Additionally, all Zika virus strains tested were sensitive to pH in the range of 6.5-6.1 and were reliant on endosomal acidification for infection. I found that Zika virus preferentially fuses with late endosomes. Comparing lineages, Zika virus enters cells in a highly conserved manner. Just as viruses have evolved to exploit host factors to promote their entry and replication, hosts have developed mechanisms of defense against viral infection. Recognition of viral infection by vertebrate hosts results in the expression and secretion of interferon. Interferon signaling subsequently results in the induction of hundreds of interferon-stimulated genes (ISGs) which restrict pathogen infection. Some of these ISGs specifically block viral entry. Surprisingly, a small group of ISGs was previously identified which actually promote viral infection. In chapter 3, I characterize the mechanism of action of MCOLN2, one of the ISGs found to promote viral infection. I assign a role for MCOLN2 in modulating viral entry. I show that MCOLN2 specifically promotes viral vesicular trafficking and subsequent escape from endosomal compartments. This mechanism requires channel activity, occurs independently of antiviral signaling, and broadly applies to enveloped RNA viruses that require endosomal acidification for infection, including influenza A virus, yellow fever virus, and Zika virus.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1255189264
dc.identifier.urihttps://hdl.handle.net/2152.5/9550
dc.language.isoenen
dc.subjectHost-Pathogen Interactionsen
dc.subjectInfluenza A virusen
dc.subjectTransient Receptor Potential Channelsen
dc.subjectVirus Internalizationen
dc.subjectYellow fever virusen
dc.subjectZika Virusen
dc.subjectZika Virus Infectionen
dc.titleCharacterization of Host Factors Affecting Viral Entryen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineMolecular Microbiologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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