**5. Therapeutic challenges and future directions**

Treatment for myocarditis mainly involves targeting the symptoms of heart dysfunction. If the disease progresses to dilated cardiomyopathy, heart transplantation is necessitated. Regrettably, for 50% of patients progressing to dilated cardiomyopathy, survival is limited to 5 years. Broad-spectrum antivirals tested in clinical trials with children and adults have been few and mildly successful. Specific therapies designed against viruses (enteroviruses) for prevention and/or management of viral myocarditis are still desperately needed. One challenge in designing specific antivirals or vaccines for viral myocarditis is the range of possible etiologies and immune mechanisms that may be responsible. Although enteroviral infection inducing or exacerbating an autoimmune response is a likely cause for viral myocarditis, supporting data defining a link between viral infection and the onset of acute and/or chronic myocarditis in humans must still be determined. The existence of many viral serotypes for promising etiological agents like coxsackievirus B also poses a problem in designing specific antiviral therapies.

Dampening the Th1 immune response in viral myocarditis is a therapeutic avenue consistently featured in past and recent studies. Many key innate immune players, such as cytokines and chemokines, are targets of potential Th1 skewing therapeutics. Cytokines presenting at the site of viral infection have a significant influence on whether a tolerant or autoimmune response is chosen. Targeting cytokines, chemokines and other immunomodulating factors for myocarditis therapy may depend on the timing and duration of the particular factor and the maintenance of immune balance to prevent the development of autoimmunity.

### **6. Conclusion**

For quite some time scientists have investigated virus and host cellular and molecular events that underlie the pathogenesis of enteroviral-induced myocarditis. Our lab has demonstrated the significance of many key innate players that contribute to coxsackievirus-B3 induced myocarditis in mouse models. Horwitz et al first revealed the importance of IFN-γ expression in the pancreas for the protection from coxsackievirus B3 infection and the induction of myocarditis (Horwitz et al. 2000). Later on, Horwitz et al again demonstrated a protective role against coxsackievirus B3-induced myocarditis with cytokine expression in the pancreas, this time, with transgenic expression of TGF-β in the beta cells (Horwitz et al. 2006). This work was followed by Richer et al, who provided a role for TLR4 and stimulation by *Salmonella minnesota* lipopolysaccharide in bypassing the protective effect exerted by TGF-β in coxsackievirus B3-induced myocarditis (Richer et al. 2006). Our lab has also investigated the role of IL-6 in disease severity. Poffenberger et al demonstrated that in the absence of IL-6, a greater early immune response occurred, instigating a severe chronic disease pathology (Poffenberger et al. 2009). Recently, Poffenberger et al described susceptibility loci on chromosome 17 that implicate the highly suggested genetic component as a factor dictating viral myocarditis pathogenesis (Poffenberger et al. 2010). Though work from our lab has contributed a great deal to the understanding of coxsackievirus B3-induced myocarditis, there remains many unanswered questions with regards to the true key immune players that dictate disease pathogenesis. It is likely that an interplay of genetic and environmental factors influence the susceptibility and severity of virus-induced myocarditis however, we must not discount the significance of the innate immune response in shaping the outcome of virus-induced disease. It is possible that this early immune response may ultimately dictate whether an acute or chronic immune response ensues with enteroviral infection.
