Acute myocarditis is a significant cause of disease in children and adults. The pathogenesis of viral myocarditis involves many interrelated processes, including direct destruction of cardiac myocytes, immune- mediated damage triggered by infection, and myocyte apotosis. Interferons are key cytokines with antiviral activity that provide protection in many models of viral myocarditis. However, many viruses have evolved mechanisms to evade host interferon responses. Associations between myocarditis and infection with human adenoviruses (Ad) have been well established, but strict species specificity limits studies of human adenovirus pathogenesis. We use mouse adenovirus type 1 (MAV-1) to study the pathogenesis of an adenovirus in its natural host. Our preliminary data suggest that 1) MAV-1 infects cardiac myocytes in vitro and hearts in vivo;2) MAV-1 induces interferon production;and 3) lymphocytes are recruited to the hearts of MAV-1-infected animals. In the experiments described in this proposal, we will use MAV-1 in neonates and adults of multiple mouse strains to establish a model of adenovirus myocarditis. We will test the overall hypothesis that a balance between viral immunomodulation and protective host factors such as the interferons determines the outcome of adenovirus myocarditis. Effective vaccines and antiviral drugs are not currently available to provide protection against adenoviruses or other viruses that typically cause viral myocarditis. Anti- inflammatory and immunomodulatory strategies have not shown consistent benefits for patients with viral myocarditis. It is therefore essential to gain a better understanding of both viral and host factors that contribute to disease in order to develop effective preventative or therapeutic strategies. MAV-1 provides a model with unique advantages for the study of adenovirus pathogenesis.
Viral infection leading to myocarditis, inflammation of the heart, is a significant disease in children and adults. The human adenoviruses are frequent causes of viral myocarditis, but very little is known regarding how host immune responses control adenovirus infections in the heart or how these immune responses may themselves contribute to the disease process. Using a mouse adenovirus to study these interactions in an animal model, we seek to define both viral and host factors that contribute to disease in order to develop effective preventative or therapeutic strategies that will benefit patients with viral myocarditis.
|McCarthy, Mary K; Malitz, Danielle H; Molloy, Caitlyn T et al. (2016) Interferon-dependent immunoproteasome activity during mouse adenovirus type 1 infection. Virology 498:57-68|
|McCarthy, Mary K; Weinberg, Jason B (2015) The immunoproteasome and viral infection: a complex regulator of inflammation. Front Microbiol 6:21|
|McCarthy, Mary K; Procario, Megan C; Twisselmann, Nele et al. (2015) Proinflammatory effects of interferon gamma in mouse adenovirus 1 myocarditis. J Virol 89:468-79|