Graduate Studies

 

Date of Award

Spring 2024

Document Type

Dissertation

Department

Integrative Biomedical Sciences

First Advisor

Jay Reddy

Abstract

Coxsackievirus Bs (CVBs) are RNA viruses of the genus Enterovirus belonging to the Picornaviridae family. CVBs commonly infect humans, and multiple CVB types can induce similar diseases such as myocarditis, pancreatitis, and type 1 diabetes (T1D). Although CVB infections can lead to the generation of autoantibodies, their role in disease is poorly defined, and vaccines are not available to prevent or minimize these infections. To fill these gaps, we first analyzed the autoantibody repertoire in mice infected with CVB3 by Phage ImmunoPrecipitation Sequencing (PhIP-Seq) and identified autoantibodies for several novel antigens not previously reported. The data were validated using enzyme-linked immunosorbent assay for select proteins, namely cytochrome c oxidase assembly factor 4 homolog and phosphoinositide-3-kinase adaptor protein 1, and their antibodies may have pathologic significance. Next, we evaluated the efficacy of the mutant (Mt)10 vaccine virus in non-obese diabetic (NOD) mice and demonstrated that Mt10 prevented CVB4-triggered T1D. However, spontaneous development of T1D in vaccinated NOD mice was not prevented, implying that the genetic predisposition to T1D cannot be altered by vaccination. Finally, by using Diversity Outbred mice as a translational model, we demonstrated that the Mt10 vaccine prevents CVB3 infection and generates neutralizing IgG antibodies. Overall, our investigations with PhIP-Seq revealed a broad spectrum of autoantibodies to cardiac and non-cardiac antigens, creating avenues to investigate their pathogenic significance. Similarly, the vaccine studies support the idea that the monovalent Mt10 vaccine virus has a potential to prevent infections caused by multiple CVBs.

Comments

Copyright 2024, Mahima Theresa Rasquinha. Used by permission

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