TRIF is a critical survival factor in viral cardiomyopathy.
TRIF is a member of the innate immune system known to be involved in viral recognition and type I IFN activation. Because IFNs are thought to play an important role in viral myocarditis, we investigated the role of TRIF in induced myocarditis in mice. Whereas C57BL/6 (wild-type) mice showed only mild myocarditis, including normal survival postinfection with coxsackievirus group B serotype 3 (CVB3), infection of TRIF(-/-) mice led to the induction of cardiac remodeling, severe heart failure, and 100% mortality (p < 0.0001). These mice showed markedly reduced virus control in cardiac tissues and cardiomyocytes. This was accompained with dynamic cardiac cytokine activation in the heart, including a suppression of the antiviral cytokine IFN-β in the early viremic phase. TRIF(-/-) myocytes displayed a TLR4-dependent suppression of IFN-β, and pharmacological treatment of CVB3-infected TRIF(-/-) mice with murine IFN-β led to improved virus control and reduced cardiac inflammation. Additionally, this treatment within the viremic phase of myocarditis showed a significant long-term outcome indexed by reduced mortality (20 versus 100%; p < 0.001). TRIF is essential toward a cardioprotection against CVB3 infection.
Department of Cardiology and Pulmology, University of Griefswald, 17475 Greifswald, Germany. alexanderriad@web.de
Alexander
A
Riad
Dirk
D
Westermann
Christin
C
Zietsch
Konstantinos
K
Savvatis
Peter M
PM
Becher
Stefan
S
Bereswill
Markus M
MM
Heimesaat
Olga
O
Lettau
Dirk
D
Lassner
Andrea
A
Dörner
Wolfgang
W
Poller
Matthias
M
Busch
Stephan B
SB
Felix
Heinz P
HP
Schultheiss
Carsten
C
Tschöpe
D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D029822:Enterovirus B, Human / Q000276:immunology* / Q000472:pathogenicity; D006367:HeLa Cells; D006333:Heart Failure / Q000276:immunology / Q000401:mortality / Q000628:therapy; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000502:physiology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D012703:Serotyping; D018487:Ventricular Dysfunction, Left / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D014779:Virus Replication / Q000276:immunology
D033942:Adaptor Proteins, Vesicular Transport; D016899:Interferon-beta; C476286:Ticam1 protein, mouse