Abstract 333: Chemokine and Autophagy-Related Genes in Novel In Vivo and In Vitro Models for Viral Myocarditis
Picornavirus infection is one of leading causes of myocarditis in humans. Theiler's murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus, the family Picornaviridae. While TMEV has been used as a mouse model for multiple sclerosis (MS), TMEV can also cause myocarditis in mice. We found that the susceptibilities of mouse strains to myocarditis differed from susceptibilities to the MS model. In the heart, we detected viral replication and inflammation. However, it is unclear whether virus itself or immune cells damaged the heart. To clarify the role of direct virus infection in myocarditis we used the cardiomyocyte cell line, HL-1, which retains a differentiated cardiomyocyte phenotype and contractile activity. We infected HL-1 with TMEV and monitored cytopathic effect (CPE) and cell viability. At 8 hours post infection (hpi), HL-1 cells developed CPE with decreased contractile activities, while cell death was not obvious. We detected 54% and 93% of cell death at 12 and 24 hpi, respectively, while no cell death was observed in mock-infection. We conducted microarray analyses to compare mRNA expression patterns between TMEV and mock-infected groups, using an Affymetrix GeneChip Mouse 1.0 ST Array. Principal component analysis (PCA) for microarray data clearly separated TMEV- and mock-infected groups (PC1 proportion of variance, 59%). TMEV infection induced high expression of several interferon-associated and chemokine genes, particularly Cxcl10/IP-10. Cxcl10 is a potent chemoattractant for activated T cells and NK cells, and its potential roles have been associated with immune cells in other myocarditis models. Our current results demonstrated that virus infection alone could induce Cxcl10 in cardiomyocytes without immune cells. We also found upregulation of autophagy-related 12 gene (Atg12). In general, autophagy can contribute to eradication of intracellular pathogens including viruses. However, since induction of autophagy by picornavirus has been shown to enhance virus replication, autophagy may also play a detrimental role in TMEV-induced myocarditis. Our novel in vivo and in vitro models of myocarditis are powerful tools to dissect the role of viral and immune pathogenesis of the heart, complementing each other.
- © 2012 by American Heart Association, Inc.