Role of the innate immune system in acute viral myocarditis.
Although the adaptive immune system is thought to play an important role in the pathogenesis of viral myocarditis, the role of the innate immune system has not been well defined. To address this deficiency, we employed a unique line of mice that harbor a genomic "knock in" of a mutated TNF gene lacking the AU rich element (TNF(ARE/ARE)) that is critical for TNF mRNA stability and translation, in order to examine the contribution of the innate immune system in encephalomyocarditis-induced myocarditis (EMCV). Heterozygous mice (TNF(ARE/+)) were infected with 500 plaque-forming units of EMCV. TNF(ARE/+)mice had a significantly higher 14-day mortality and myocardial inflammation when compared to littermate control mice. Virologic studies showed that the viral load at 14 days was significantly lower in the hearts of TNF(ARE/+) mice. TNF(ARE/+) mice had an exaggerated proinflammatory cytokine and chemokine response in the heart following EMCV infection. Modulation of the innate immune response in TNF(ARE/+) mice by the late administration of prednisolone resulted in a significant improvement in survival and decreased cardiac inflammation, whereas early administration of prednisolone resulted in a blunted innate response and increased mortality in littermate control mice. Viewed together, these data suggest that the duration and degree of activation of the innate immune system plays a critical role in determining host outcomes in experimental viral myocarditis.
Huang
Chien-Hua
CH
Winters Center for Heart Failure Research, Houston, TX 77030, USA.
Vallejo
Jesus G
JG
Kollias
George
G
Mann
Douglas L
DL
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018188:Cardiovirus Infections / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D004686:Encephalomyocarditis virus; D005260:Female; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D006321:Heart / Q000821:virology; D007113:Immunity, Innate; D008297:Male; D051379:Mice; D009205:Myocarditis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D019562:Viral Load
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D011239:Prednisolone