Abstract 18172: FOXO3a Controls Viral Load in Acute Coxsackievirus B3 Myocarditis - Role of NK Cell Function
Purpose: Coxsackievirus B3 is known to induce myocarditis leading to dilative cardiomyopathy and heart failure. Cardiac injury is mediated by both direct viral damage and the hosts immune response. FOXO transcription factors are activated by stress and play key roles in immunoregulation and stress resistance. We therefore investigated the role of FOXO3a in CVB3 myocarditis.
Methods: CVB3 myocarditis was induced in WT and FOXO3a-/- mice. Myocardial mRNA expression was assessed by qRT-PCR. Myocardial viral load was assessed by plaque assay. Hearts were stained with hematoxylin/eosin and evaluated for myocarditis by inflammatory score. NK cells were analyzed for cytotoxicity, IFNγ production and activation markers ex vivo by FACS.
Results: FOXO3a-/- mice showed significantly better cardiac viral clearance compared to wild-type mice at 7d p.i. (p<0.01) accompanied by a reduced inflammatory score (p<0.05) and diminished expression of CD3, CD4, CD14 cells. Moreover, cardiac expression of TNFα, IFNβ and IFNγ was significantly attenuated in FOXO3a-/- mice. Importantly, myocardial mRNA expression of CAR was not different in both groups (p=NS). In vitro, FOXO3a gene transfer had no effect on viral adhesion, entry or replication in cardiac myocytes (p=NS). At d3 p.i. however, CVB3 titers were not significantly different in hearts and pancreas in Foxo3a-/- and WT mice. Interestingly, increased numbers of Nkp46+ NK cells were detected in the hearts and spleen of FOXO3a-/- mice together with higher mRNA expression of IFNy. Moreover, NK cells isolated from FOXO3a-/- mice had an enhanced cytotoxic activity with higher frequencies of activated effector NK cells and showed enhanced production of IFNγ ex vivo (p<0.05). Accordingly, Foxo3a-/- mice showed enhanced LV-Function and incraesed LV-contractility (dP/dtmax) at d7 p.i. (p<0.05).
Conclusion: Our results implicate FOXO3a directly in the immune response to viral myocarditis leading to myocardial viral clearance and containment of inflammation. Thus, enhanced function of NK cells in FOXO3a-/- mice increase the acute anti-viral immune response in CVB3-myocarditis.
- © 2012 by American Heart Association, Inc.