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SARS-COV-2 PATHOGENESIS AND THE HOST IMMUNE RESPONSE

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dc.contributor.authorImbiakha, Brian
dc.contributor.chairAguilar-Carreno, Hectoren_US
dc.contributor.committeeMemberAugust, Averyen_US
dc.contributor.committeeMemberRudd, Brianen_US
dc.contributor.committeeMemberParker, Johnen_US
dc.date.accessioned2024-04-05T18:46:54Z
dc.date.issued2023-08
dc.description142 pagesen_US
dc.description.abstractSARS-CoV-2 is the causative agent of the ongoing CoVID-19 pandemic. It was initially reported in December 2019 when a cluster of viral associated pneumonia cases were reported among individuals who had visited a seafood market in Wuhan, Hubei province, China. The original Wuhan strain underwent rapid mutations, giving rise to multiple variants of concern (VOC), including alpha, beta, gamma, and delta, which displayed high pathogenicity, leading to severe disease and fatalities both in humans and animal models. Severe disease is defined by immune dysregulation, marked by elevated expression of pro-inflammatory cytokines such as IL-6 and TNF-α. In November 2021, a new variant, B.1.1.529 (Omicron), emerged in South Africa. Omicron demonstrated increased transmissibility compared to the previously predominant delta variant, however, it was significantly attenuated. With time, Omicron gave rise to multiple variants, including Omicron BA.2. Although Omicron BA.2 was deemed non-lethal in animal models of disease, it was associated with high fatality rates among a group of individuals in Hong Kong who were either non-vaccinated or had received only a single dose of the vaccine. Another notable variant, Omicron BA.5, emerged and exhibited characteristics of high transmissibility and superior replication in vitro compared to both Omicron BA.1 and BA.2. The in vivo characteristics of Omicron BA.5 and role of adaptive immunity in SARS-CoV-2 pathogenicity remain incompletely characterized. This thesis investigates the pathogenesis of both severe and moderate disease caused by SARS-CoV-2. First, it characterizes the pathogenesis of the Omicron BA.5 variant, reporting that Omicron BA.5 causes morbidity and mortality in K18-hACE-2 mice. Through rigorous investigation, we seek to shed light on the underlying mechanisms and factors driving this unexpected pathogenicity. Secondly, we explore a novel role for the adaptive immune response in relation to mouse adapted SARS-CoV-2 (SARS-CoV-2 MA10) induced pathogenicity. We show that the adaptive immunity is necessary for SARS-CoV-2 MA10 induced pathology. Additionally, we establish a novel model to investigate viral persistence and evolution in immunocompromised mice. In the integration of these two research avenues, this thesis seeks to expand our understanding of SARS-CoV-2 infection, from pathogenesis, to viral determinants of pathogenicity and virus induced immunopathology.en_US
dc.description.embargo2025-09-05
dc.identifier.doihttps://doi.org/10.7298/fwwj-hr68
dc.identifier.otherImbiakha_cornellgrad_0058F_13855
dc.identifier.otherhttp://dissertations.umi.com/cornellgrad:13855
dc.identifier.urihttps://hdl.handle.net/1813/114659
dc.language.isoen
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectImmune dysregulationen_US
dc.subjectImmunopathologyen_US
dc.subjectOmicronen_US
dc.subjectSARS-CoV-2en_US
dc.subjectSARS-CoV-2 MA10en_US
dc.subjectViral pathogenesisen_US
dc.titleSARS-COV-2 PATHOGENESIS AND THE HOST IMMUNE RESPONSEen_US
dc.typedissertation or thesisen_US
dcterms.licensehttps://hdl.handle.net/1813/59810.2
thesis.degree.disciplineBiomedical and Biological Sciences
thesis.degree.grantorCornell University
thesis.degree.levelDoctor of Philosophy
thesis.degree.namePh. D., Biomedical and Biological Sciences

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