Abstract 752: Role of the Innate Immune Response in Viral Myocarditis
Background: The innate immune system enables the host to deal quickly and efficiently with invading microorganisms. However, little is known with regard to the role of innate immune mechanisms in the pathogenesis of viral myocarditis. We studied mice that harbor a genomic “knock in” of a mutated TNF gene lacking the AU rich element (TNFΔARE/ΔARE) that is critical for TNF mRNA stability and translation to examine the contribution of the innate immune system in encephalomyocarditis (EMCV)-induced myocarditis..
Methods: Wild-type (WT) and heterozygous mice (TNFΔARE/Δ) mice were infected (i.p.) with 500 pfu of EMCV. Cardiac EMCV genomic RNA levels and viral load were determined after infection. Hearts from both groups were examined for evidence of cellular infiltration. Cardiac TNF, IL-1β, and IFNβ gene expression were assessed by RNAse protection assay.
Results: The 14 day survival rate was significantly reduced in TNFΔARE/Δmice compared to WT controls (12.5% vs. 49%; P<0.05). EMCV genomic RNA levels and viral load were significantly higher in the hearts of WT mice (2.4±0.13 log10 PFU/mg heart vs. 1.17± 0.30 log10 PFU/mg; P<0.05) compared to TNFΔARE/Δmice . Histopathologic examination revealed that the inflammatory response in the heart was significantly increased in TNFΔARE/Δmice compared to controls. TNFΔARE/Δ mice had an exaggerated proinflammatory cytokine response in the heart following EMCV infection. There was a 14-fold (p <0.05) increase in TNF protein levels and a 6-fold (p < 0.05) increase in IL-1β levels in the hearts of TNFΔARE/Δ mice relative to EMCV infected controls. No difference in IFNβ production was noted. Administration of prednisolone (days 7–14 of infection) resulted in a significant improvement in survival and decreased cardiac inflammation in TNFΔARE/Δ mice, whereas no difference was observed in WT mice.
Conclusion: The results of this study suggest that activation of the innate immune system plays an important role in the early host response to viral infection by controlling viral replication, whereas sustained activation of the innate immune response can contribute to myocardial damage through excessive activation of the acquired immune system.