Abstract
BackgroundMyocarditis is an inflammation of the myocardium that often follows the enterovirus infections, with coxsackievirus B3 (CVB3) being the most dominant etiologic agent. We and other groups previously reported that chemokine IP-10 was significantly induced in the heart tissue of CVB3-infected mice and contributed to the migration of massive inflammatory cells into the myocardium, which represents one of the most important mechanisms of viral myocarditis. To evaluate the direct effect of IP-10 on the inflammatory responses in CVB3 myocarditis, herein an IP-10 mutant deprived of chemo-attractant function was introduced into mice to antagonize the endogenous IP-10 activity, and its therapeutic effect on CVB3-induced myocarditis was evaluated.Methodology/Principal FindingsThe depletion mutant pIP-10-AT, with an additional methionine after removal of the 5 N-terminal amino acids, was genetically constructed and intramuscularly injected into BALB/c mice after CVB3 infection. Compared with vector or no treatment, pIP-10-AT treatment had significantly reduced heart/body weight ratio and serum CK-MB level, increased survival rate and improved heart histopathology, suggesting an ameliorated myocarditis. This therapeutic effect was not attributable to an enhanced viral clearance, but to a blunted Th1 immune response, as evidenced by significantly decreased splenic CD4+/CD8+IFN-γ+ T cell percentages and reduced myocardial Th1 cytokine levels.Conclusion/SignificanceOur findings constitute the first preclinical data indicating that interfering in vivo IP-10 activity could ameliorate CVB3 induced myocarditis. This strategy may represent as a new therapeutic approach in treating viral myocarditis.
Highlights
Viral myocarditis represents a leading cause of sudden death in young adults
To understand whether inducible protein 10 (IP-10) play a role in coxsackievirus B3 (CVB3)-induced myocarditis, the kinetic expression of IP-10 following CVB3 infection was first observed
BALB/c mice were infected with 103 TCID50 dose of CVB3 for various time periods or with different CVB3 doses for 4 days, the heart tissues were collected, homogenized and subjected to ELISA assays
Summary
Viral myocarditis represents a leading cause of sudden death in young adults. Up to 20% of patients with histological evidence of myocarditis will develop dilated cardiomyopathy, a fatal disease leaving heart transplantation as the only treatment [1,2,3]. The murine model of CVB3-induced myocarditis has been developed that shares many characteristics with human disease. Studies in the murine CVB3 myocarditis model have found that CVB3 can directly destroy myocardium, the strong host Th1 immune responses may play a more critical pathogenetic role in the course of viral myocarditis, verified by the improvement of heart injury and function by immune modulating and inhibiting agents [4,5,6]. Myocarditis is an inflammation of the myocardium that often follows the enterovirus infections, with coxsackievirus B3 (CVB3) being the most dominant etiologic agent. We and other groups previously reported that chemokine IP-10 was significantly induced in the heart tissue of CVB3-infected mice and contributed to the migration of massive inflammatory cells into the myocardium, which represents one of the most important mechanisms of viral myocarditis. To evaluate the direct effect of IP-10 on the inflammatory responses in CVB3 myocarditis, an IP-10 mutant deprived of chemo-attractant function was introduced into mice to antagonize the endogenous IP-10 activity, and its therapeutic effect on CVB3-induced myocarditis was evaluated
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