Date of Award

2026

Embargo Period

4-6-2031

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Henry M. Sucov

Second Advisor

Donald R. Menick

Third Advisor

Kristine Y. Deleon-Pennell

Fourth Advisor

Eric G. Meissner

Fifth Advisor

Ge Tao

Abstract

Myocarditis is a highly prevalent disease characterized by excessive immune infiltration into the heart. Though there are several etiologies of myocarditis, viral infection is the most common cause. The clinical spectrum and severity of disease is highly variable between individuals, ranging from asymptomatic disease to heart failure or sudden cardiac death. Studies using inbred mice demonstrate the importance of host genetics on disease course. Using forward genetics to compare inbred mouse strains that were sensitive or resistant to severe disease, a previous study mapped the viral myocarditis susceptibility locus Vms1. Here, we demonstrate that Tnni3k, one of the genes within the Vms1 locus that encodes a cardiomyocyte-specific kinase, influences the severity of viral myocarditis.

Disease-resistant C57BL/6J wild-type mice and strain-matched Tnni3k knockout mice were infected with coxsackievirus B3. At the peak of myocarditis (8 days post-infection), we showed that Tnni3k is cardioprotective, as mutant mice experienced more severe myocarditis. We saw no long-term consequences of severe disease, suggesting Tnni3k does not affect the chronic phase of disease. By infecting a second mouse line engineered to express kinase-dead Tnni3k, we showed that kinase activity is necessary for Tnni3k’s cardioprotection.

We next sought to identify the cardiomyocyte-specific mechanisms by which Tnni3k acts. A bulk RNA-seq analysis in uninfected animals suggested Tnni3k enhances type I interferon signaling. This was confirmed in a HEK293 cell-based transient transfection assay. The in vivo infection model further supported Tnni3k’s role in the type I interferon pathway, as wild-type animals maintained higher production of type I interferons over the course of infection. A bulk RNA-seq analysis in infected animals emphasized tissue-wide consequences of increased inflammation in mutant animals, though failed to capture Tnni3k’s role in cardiomyocytes.

Altogether, we identified Tnni3k and its kinase activity as being protective in modulating the acute phase of inflammatory response, with particular attention to type I interferons, to coxsackieviral infection of the heart. Human mutations in Tnni3k have been well documented and millions of people may be disproportionately affected by severe disease. This work provides further insight into a genetic controller of viral myocarditis and highlights a possible mechanism for Tnni3k.

Rights

Copyright is held by the author. All rights reserved.

Download

Available for download on Sunday, April 06, 2031

Share

COinS