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UBC Theses and Dissertations

Coxsackievirus-induced myocarditis : identifying disease mediators Poffenberger, Maya Chikako


Myocarditis-induced dilated cardiomyopathy is a major cause of heart disease and sudden death in young adults. Development of myocarditis is thought to involve both genetic and environmental factors such as pathogen infection, with the most commonly associated pathogen being the enterovirus coxsackievirus. Herein is a summary of three research projects aimed at identifying genes associated with coxsackievirus-induced myocarditis. In the first project, the role of IL-6 in coxsackievirus-induced myocarditis was investigated. IL-6 was found to have a protective role in disease development as IL-6 deficient mice developed increased chronic disease pathology following viral infection. Recombinant IL-6 treatment in these mice decreased the disease severity, suggesting that IL-6 production during the initiation of the disease regulates myocarditis severity. The second research project was aimed at identifying genetic loci that confer susceptibility to coxsackievirus-induced myocarditis. Using chromosome substitution mouse strains (CSS) and congenic mice generated from the CSS mice, three loci on chromosome 17 were shown to confer susceptibility to chronic myocarditis. Two of the loci, Vam1 and Vam2, do not contain any genes previously associated with myocarditis development. Real-time PCR analysis identified Igf2r and Cacna1h to be strong candidates for the susceptibility genes in the Vam1 and Vam2 loci, respectively. In the third research project, the immune response following coxsackievirus infection was monitored in four inbred mouse strains in order to identify immune factors involved in disease development. Three of the strains, A/J, NOD and BALB/c, were susceptible to disease while the fourth strain, C57BL/6, was resistant to disease. Two interesting responses were observed. The first was increased TNFα levels in the resistant mice and the second was increased PD-L1 expression in the susceptible mice. Administered recombinant TNFα to the susceptible A/J mice was sufficient to increase their survival, indicating a disease protective role for TNFα in virus-induced myocarditis. All together, these data indicate that a network of many genes, both immune and non-immune, is involved in myocarditis development following virus infection. Identifying and elucidating the role of these genes in myocarditis induction could suggest ways to limit disease progression by developing therapies to target these disease modifiers.

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