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Abstract: IL-17-producing (Th17) and regulatory T (Treg) cells have been well established in the pathogenesis of many inflammatory diseases. To assess whether Th17 and Treg were altered in acute virus-induced myocarditis (AVMC) mice, we assessed Th17/Treg functions on different levels in AVMC. It was shown that the expression of splenic Th17 cells and Th17-related cytokines (IL-17A, IL-21) markedly increased. Interestingly, the expression of splenic Treg cells and Treg-related cytokines (TGF-β, IL-10) also significantly increased. Using neutralization of IL-17 in the AVMC, we found that Treg cells roughly decreased compared with isotype control mice. However, T cells and perforin dramatically increased, followed by a marked reduction in CVB3 replication. The results suggested that Th17 cells possibly contributed to viral replication through the action of Treg cells in mediating T cells and perforin response in AVMC. [Copyright &y& Elsevier]

Abstract: Coxsackievirus B3 (CVB3) is a gastrointestinal virus causing myocarditis in human and mice. An ideal vaccine for CVB3-myocarditis requires both humoral and cellular immunity at systemic and mucosal compartments. We described here an enhancing strategy for chitosan-pVP1 vaccine by co-immunizing with lymphotactin (LTN) gene, a T cell-attractive-chemokine, encapsulated in chitosan particle to provide more protection against CVB3. Mice were intranasally co-immunized with 4 doses of chitosan–DNA vaccines separately encapsulating VP1 and LTN plasmids by 2 week-intervals and challenged with CVB3 4 weeks after the last immunization. Compared with chitosan-pVP1 alone, co-immunization with chitosan-pLTN significantly increased high-avidity-neutralizing antibody levels in serum and in intestinal mucosa, and promoted systemic and mucosal Th1 and CD8+CTL immune responses. Accordingly, enhanced resistance to CVB3-myocarditis was evidenced by reduced myocardial viral load, profound subsidence of myocarditis and increased survival rate. This strategy represents a promising platform for Th1 polarization and protection against mucosal infectious pathogens. [Copyright &y& Elsevier]

Viral myocarditis is an important human disease, and reovirus-induced myocarditis in mice provides an excellent model to study direct viral damage to the heart. Previously, we showed that reovirus induction of and sensitivity to interferon-β (IFN-β) is an important determinant of viral pathogenicity in the heart and that the transcription factor interferon regulatory factor-3 (IRF-3) is required for reovirus induction of IFN-β in primary cardiac myocyte cultures. Given several lines of evidence suggesting a possible distinctive environment for IRFs in the heart, we have now focused on IRF-1. Previous studies demonstrated that viruses, double-stranded-RNA (dsRNA), and IFN-α/β can each induce IRF-1 and that IRF-1 plays a role in dsRNA, but perhaps not viral, induction of IFN-α/β. Importantly, none of these studies used a virus with a dsRNA genome (such as reovirus), none of them used a highly differentiated nonlymphoid cell type, and none of them addressed whether viral induction of IRF-1 is direct or is mediated through viral induction of IFN-β. Indeed, as recently as this year it has been assumed that viral induction of IRF-1 is direct. Here, we found that reovirus induced IRF-1 in primary cardiac myocyte cultures, but that IRF-1 was not required for reovirus induction of IFN-β. Surprisingly, we found that reovirus failed to induce IRF-1 in the absence of the IFN-α/β response. This provides the first evidence that viruses may not induce IRF-1 directly. Finally, nonmyocarditic reovirus strains induced more cardiac lesions in mice deficient for IRF-1 than they did in wildtype mice, directly demonstrating a protective role for IRF-1. Together, the results indicate that while IRF-1 is downstream of the IFN-β response, it plays an important protective role against viral myocarditis. [Copyright &y& Elsevier]