Sherry B, Torres J, Blum M A
Department of Microbiology, Pathology, and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh 27606, USA.
J Virol. 1998 Feb;72(2):1314-23. doi: 10.1128/JVI.72.2.1314-1323.1998.
Reovirus-induced acute myocarditis in mice serves as a model to investigate non-immune-mediated mechanisms of viral myocarditis. We have used primary cardiac myocyte cultures infected with a large panel of myocarditic and nonmyocarditic reassortant reoviruses to identify determinants of viral myocarditic potential. Here, we report that while both myocarditic and nonmyocarditic reoviruses kill cardiac myocytes, viral myocarditic potential correlates with viral spread through cardiac myocyte cultures and with cumulative cell death. To address the role of secreted interferon (IFN), we added anti-IFN-alpha/beta antibody to infected cardiac myocyte cultures. Antibody benefited nonmyocarditic more than myocarditic virus spread (P < 0.001), and this benefit was associated with the reovirus M1 and L2 genes. There was no benefit for a differentiated skeletal muscle cell line culture (C2C12 cells), suggesting cell type specificity. IFN-beta induction in reovirus-infected cardiac myocyte cultures correlated with viral myocarditic potential (P = 0.006) and was associated with the reovirus M1, S2, and L2 genes. Sensitivity to the antiviral effects of IFN-alpha/beta added to cardiac myocyte cultures also correlated with viral myocarditic potential (P = 0.004) and was associated with the same reovirus genes. Several reoviruses induced IFN-beta levels discordant with their myocarditic phenotypes, and for those tested, sensitivity to IFN-alpha/beta compensated for the anomalous induction levels. Thus, the combination of induction of and sensitivity to IFN-alpha/beta is a determinant of reovirus myocarditic potential. Finally, a nonmyocarditic reovirus induced cardiac lesions in mice depleted of IFN-alpha/beta, demonstrating that IFN-alpha/beta is a determinant of reovirus-induced myocarditis. This provides the first identification of reovirus genes associated with IFN induction and sensitivity and provides the first evidence that IFN-beta can be a determinant of viral myocarditis and reovirus disease.
呼肠孤病毒诱导的小鼠急性心肌炎可作为研究病毒性心肌炎非免疫介导机制的模型。我们使用原代心肌细胞培养物，用大量心肌炎型和非心肌炎型重配呼肠孤病毒感染，以确定病毒心肌炎潜力的决定因素。在此，我们报告，虽然心肌炎型和非心肌炎型呼肠孤病毒均可杀死心肌细胞，但病毒心肌炎潜力与病毒在心肌细胞培养物中的传播以及累积细胞死亡相关。为了探讨分泌型干扰素（IFN）的作用，我们向感染的心肌细胞培养物中添加了抗IFN-α/β抗体。抗体对非心肌炎型病毒传播的促进作用大于心肌炎型病毒（P < 0.001），且这种促进作用与呼肠孤病毒M1和L2基因有关。对分化的骨骼肌细胞系培养物（C2C12细胞）则无促进作用，提示细胞类型特异性。呼肠孤病毒感染的心肌细胞培养物中IFN-β的诱导与病毒心肌炎潜力相关（P = 0.006），且与呼肠孤病毒M1、S2和L2基因有关。对添加到心肌细胞培养物中的IFN-α/β抗病毒作用的敏感性也与病毒心肌炎潜力相关（P = 0.004），且与相同的呼肠孤病毒基因有关。几种呼肠孤病毒诱导的IFN-β水平与其心肌炎表型不一致，对于所测试的病毒，对IFN-α/β的敏感性弥补了异常的诱导水平。因此，IFN-α/β的诱导和敏感性的组合是呼肠孤病毒心肌炎潜力的决定因素。最后，一种非心肌炎型呼肠孤病毒在IFN-α/β缺失的小鼠中诱导了心脏病变，表明IFN-α/β是呼肠孤病毒诱导的心肌炎的决定因素。这首次鉴定了与IFN诱导和敏感性相关的呼肠孤病毒基因，并首次证明IFN-β可以是病毒性心肌炎和呼肠孤病毒疾病的决定因素。
