Antiviral effects of interferon-β are enhanced in the absence of the translational suppressor 4E-BP1 in myocarditis induced by Coxsackievirus B3

Background: Viral myocarditis is most frequently associated with infection by Coxsackievirus B3 (CVB3). Interferon (IFN)-beta therapy has been studied and could reduce virally induced tissue damage and improve heart function. Methods: In the present study we have investigated the role of translational suppression in the context of an IFN-alpha/beta-mediated antiviral immune response to CVB3 infection. Specifically, we examined the effects of IFN-alpha/beta treatment of CVB3-infected mouse embryonic fibroblast cells and splenocytes lacking eukaryotic initiation factor 4E binding protein-1 (4E-BP1), a suppressor of 5'-capped mRNA translation. Extending these in vitro studies, we examined the effects of CVB3 infection and IFN-beta treatment in 4E-BP1(-/-) mice. Results: Our data show that 4E-BP1(-/-) cells are more sensitive to the antiviral effects of IFN-alpha 4 and IFN-beta treatment than 4E-BP1(+/+) cells when infected with CVB3. Similarly, 4E-BP1(-/-) mice are more sensitive to treatment with IFN-beta, exhibiting lower viral titres in heart tissue than 4E-BP1(+/+) mice during the course of infection. Additionally, we demonstrate that treatment with IFN-beta reduces inflammatory infiltrates into the hearts of infected mice. Conclusions: These data identify 4E-BP1 as a novel drug target to augment responsiveness to IFN-beta therapy in CVB3-induccd myocarditis.