Studying Emerging Zoonotic Viruses: from Pathogenicity Characterization to the Development of Vaccines and Therapeutics in Animal Models
Access to this document is restricted. Some items have been embargoed at the request of the author, but will be made publicly available after the "No Access Until" date.
During the embargo period, you may request access to the item by clicking the link to the restricted file(s) and completing the request form. If we have contact information for a Cornell author, we will contact the author and request permission to provide access. If we do not have contact information for a Cornell author, or the author denies or does not respond to our inquiry, we will not be able to provide access. For more information, review our policies for restricted content.
Emerging zoonotic viruses pose a critical challenge to global public health due to their capacity to incite pandemics and overwhelm healthcare systems. This thesis focuses on understanding viral pathogenicity and developing innovative therapeutic and preventive strategies. Utilizing transgenic animal models, we explored the dynamics of pathogenicity among SARS-CoV-2 variants and expanded our scope to other high-priority zoonotic viruses, including Nipah, Hendra, and Ebola. In-depth studies of SARS-CoV-2 revealed distinct pathogenic mechanisms among Omicron subvariants BA.1, BA.4 and BA.5. While BA.1and BA.4 exhibited limited pathology, BA.5 demonstrated significantly higher virulence, characterized by severe respiratory pathology, cytokine dysregulation, and age-dependent lethality in K18-hACE2 transgenic mice. A key finding was the role of non-structural protein 1 (NSP1) in modulating host immune responses. A triple amino acid deletion (KSF) in NSP1, observed in BA.4 but absent in BA.5, was identified as a determinant of reduced virulence. Recombinant BA.5 expressing BA.4 NSP1 displayed attenuated pathogenicity, highlighting NSP1 as a potential target for therapeutic intervention. Beyond SARS-CoV-2, the development of broad-spectrum antivirals (BSAs) and multivalent vaccines emerged as pivotal strategies to combat a range of viral threats. We identified synthetic carbohydrate receptors (SCRs) as potent BSAs, demonstrating efficacy across six viral families, including Coronaviridae, Paramyxoviridae, and Filoviridae. SCR005 and SCR007 exhibited robust antiviral activity with minimal toxicity, targeting conserved N-glycans on viral glycoproteins to prevent host cell entry. In parallel, we designed a multivalent vesicular stomatitis virus (VSV)-based vaccine platform incorporating glycoproteins from Nipah, Hendra, and Ebola viruses. This vaccine elicited durable immune responses and provided complete protection in swine and rodent models. The incorporation of trehalose-based adjuvants further enhanced immunogenicity while maintaining safety profiles. This research advances our understanding of viral pathogenesis and offers innovative approaches to therapeutic and vaccine development. By elucidating molecular determinants of virulence and leveraging conserved viral features, we lay the groundwork for broad-spectrum solutions to current and future zoonotic threats. These findings hold significant promise for enhancing global preparedness against pandemics.