Author + information
- Carsten Skurk,
- Madlen Loebel,
- Luise Holzhauser,
- Moritz Becher,
- Sandra Pinkert,
- Heinz-Peter Schultheiss and
- Carmen Scheibenbogen
Coxsackievirus B3 is known to induce myocarditis leading to dilative cardiomyopathy and heart failure. Cardiac injury is mediated by both direct damage by the virus and the hosts immune response. FOXO transcription factors are activated by stress and play key roles in immunoregulation and stress resistance, including anti-inflammatory effects via inhibition of NFκB. We therefore investigated the role of FOXO3a in CVB3 myocarditis.
CVB3 myocarditis was induced in WT and FOXO3a-/- mice. mRNA/miRNA expression, SNP analysis and viral load was assessed by QRT-PCR. Hearts were stained with hematoylin/eosin and evaluated for myocarditis by inflammatory score. NK cells were analyzed for cytotoxicity, IFN-γ production and activation markers by fluorescence activated cell sorting.
FOXO3a-/- mice showed significantly lower viral titers compared to wild-type mice at 3d and 7d p.i. accompanied by a reduced inflammatory score (p<0.05) and diminished expression of CD3+ T cells, CD14+ monocytes. as well as Nkp46+ cells. Moreover, expression of pro-inflammatory cytokines was diminished in FOXO3a-/- mice at 7d p.i.. Importantly, there was no difference in myocardial mRNA expression of Coxsackievirus B3 receptor. Interestingly, FOXO3a gene transfer in vitro had no effect on viral adhesion and entry but significantly inhibited CVB3 replication in cardiac myocytes. Ex vivo, NKp46+ NK cells of FOXO3a-/- mice showed a higher activation status and enhanced cytotoxic activity with higher frequencies of activated CD69+ and CD27+CD11b+ effector NK cells as well as enhanced expression of IFN-γ accompanied by an upregulation of miR-155 (p<0.05). Moreover, the analysis of healthy human donors for the gain of function FOXO3a SNP rs9400239 revealed a significantly reduced CD107a dependent degranulation activity in donors homozygous for the allelic variant.
Our results implicate FOXO3a directly in the response to viral myocarditis leading to lower myocardial viral titers and inflammation. Increased function of NK cells in FOXO3a-/- mice may play a crucial role in the defence against CVB3 myocarditis.
Poster Sessions, Expo North
Sunday, March 10, 2013, 9:45 a.m.-10:30 a.m.
Session Title: Myocarditis: Mechanistic Insights
Abstract Category: 23. Pericardial/Myocardial Disease
Presentation Number: 1207-147
- 2013 American College of Cardiology Foundation