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dc.contributor.advisorBarton, David J.
dc.contributor.advisorMorrison, Thomas E.
dc.contributor.authorHawman, David
dc.contributor.committeememberBeckham, John D.
dc.contributor.committeememberSantiago, Mario L.
dc.contributor.committeememberTorres, Raul M.
dc.date.accessioned2017-01-06T22:35:00Z
dc.date.available2018-12-19T08:20:26Z
dc.date.submitted2016
dc.descriptionIncludes bibliographical references.
dc.descriptionFall
dc.description.abstractChikungunya virus (CHIKV) is a mosquito-transmitted arthritogenic alphavirus that is a global public health burden. In 2013, CHIKV spread from the Eastern Hemisphere to the Americas where it has since spread to 45 countries and territories in the region and caused nearly two million cases. CHIKV disease in humans is debilitating, and characterized by a sudden onset of high fever, severe joint pain and inflammation. More severe outcomes, including death, occur in neonates, the elderly, and in those with underlying medical co-morbidities. In many patients, disease signs and symptoms, including joint pain, inflammation, swelling, and stiffness, as well as tenosynovitis, can last for months to years. Despite the global spread of CHIKV, the pathogenesis of chronic CHIKV disease is not well understood. A limited body of evidence suggests that CHIKV, and related arthritogenic alphaviruses, establish long-term persistent infections in musculoskeletal tissues. Therefore, critically unanswered questions are whether chronic CHIKV disease is due to chronic infection, and if so, how does CHIKV evade seemingly robust innate and adaptive antiviral immune responses. To investigate persistent CHIKV infection, I used a mouse model that recapitulates many aspects of acute CHIKV disease and demonstrated that CHIKV infection persisted specifically in joint-associated tissue for at least 16 weeks, and that viral persistence was associated with chronic synovitis. By performing parallel infection studies in WT and immunodeficient mice, I showed that adaptive immune responses play a critical role in controlling rather than contributing to chronic disease pathogenesis. In additional studies, I identified two strains of CHIKV, that differ at only five amino acid positions, with distinct outcomes in immunocompetent mice; namely long term persistence versus acute clearance. In detailed mapping studies, I found that a highly conserved glycine residue at amino acid position 82 in the CHIKV E2 glycoprotein promotes viral persistence and diminishes the potency of viral neutralization by human and murine antibodies that specifically target the E2 B domain. In contrast, an arginine at this position promotes viral clearance in joints of WT but not B cell-deficient mice and enhances viral neutralization. Finally, to investigate if persistence of CHIKV is associated with the acquisition of adaptive mutations, I isolated and characterized a strain of CHIKV from the serum of persistently infected Rag1-/- mice, which have an intact innate immune response but lack mature T and B cells. I found that polymorphisms in the E2 glycoprotein and 3′ untranslated region of this strain enhanced early viral dissemination and viral virulence in naïve WT mice, suggesting that these mutations promote evasion of innate immune responses of mice. The research presented in this thesis expands our understanding of chronic CHIKV disease pathogenesis, describes new mechanisms by which pathogenic strains of CHIKV evade antiviral antibody responses to establish a persistent infection in joint-associated tissues, and identifies viral determinants selected during long-term persistence in mice. Collectively, this work provides new insights into the biological basis of chronic arthritis associated with CHIKV infection, mechanisms of chronic CHIKV infection, and will aid in the development of vaccines and antibody-based therapeutics against CHIKV.
dc.identifierHawman_ucdenveramc_1639D_10363.pdf
dc.identifier.schemaETD Data Dictionary 1.1
dc.identifier.urihttp://hdl.handle.net/10968/1747
dc.languageEnglish
dc.publisherUniversity of Colorado Anschutz Medical Campus. Strauss Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 12/19/2018
dc.subjectPathogenesis
dc.subjectPersistence
dc.subject.meshB-Lymphocytes
dc.subject.meshAlphavirus
dc.subject.meshChikungunya virus
dc.titleViral and host determinants of Chikungunya virus persistence
dc.typeThesis
dcterms.embargo.expires2018-12-19
thesis.degree.disciplineMicrobiology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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