Therapeutic efficiency of vector-expressed soluble virus receptor proteins in cardiac enterovirus infections

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Coxsackieviruses (CV) are the most common infectious agents causing virus-induced myocarditis. A specific CV therapy, however, is currently not yet available. The development of new therapeutic strategies is therefore of high relevance and represents the main objective of this project proposal. In the first funding period we have shown that a soluble CV receptor protein (sCAR-Fc) expressed from a viral vector inhibits acute CVB3 myocarditis and the development of cardiac dysfunction in vivo. Moreover, application of sCAR-Fc was sufficient to cure a newly established persistently CVB3-infected myocardial cell line. In a further study we have demonstrated that the efficiency of sCAR-Fc therapy can be improved by concomitant administration of anti-CVB3 siRNAs. Finally, we have shown for the first time that CVB3-induced myocarditis can be improved by cell therapy with mesenchymal stem cells and cardiac adherent proliferating cells.The project proposal for the second funding period involves five complexes with the following aims. (I) After having demonstrated the effectiveness of sCAR-Fc therapy in acute CVB3-induced myocarditis, we now want to investigate the therapeutic potential of sCAR-Fc in chronic myocarditis. (II) Virus-induced as well as reactive immunologic mechanisms are important mechanisms for the development of chronic CVB3-induced myocarditis. We will determine the extent to which the combination of antiviral therapy with sCAR-Fc and immunosuppressive pharmacotherapy and immunomodulatory stem cell therapy results in an improvement of the therapeutic efficiency. (III) Picornaviruses, among them CVB3, rapidly develop escape mutants following pharmacotherapy. However, there are thus far no studies investigating the occurrence of sCAR-Fc-resistant CVB3 mutants. We intend to analyze CVB3 isolates from sCAR-Fc-treated, CVB3-infected mice for sCAR-Fc-resistant mutants. Furthermore, sCAR-Fc escape mutants will be deliberately generated in vitro and the mechanisms for the development of resistance will be investigated. (IV) We have shown that the D2 domain of CAR, which is not directly involved in binding to CVB3, is important for the CVB3 neutralizing properties of sCAR-Fc. We will further elucidate the function of the D2 domain and the involved mechanisms. (V) Finally, since there are no data available to date, we intend to investigate CVB3 isolates from patients for susceptibility to sCAR-Fc. The expected results may be highly relevant for a potential clinical therapeutic application of sCAR-Fc.