Combination of RNA interference and virus receptor trap exerts additive antiviral activity in coxsackievirus B3-induced myocarditis in mice.
Combination of RNA interference and virus receptor trap exerts additive antiviral activity in coxsackievirus B3-induced myocarditis in mice.
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DOI：
10.1093/infdis/jiu504
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发表时间：
2015-02
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通讯作者：
E. A. Stein;S. Pinkert;P. Becher;Anja Geisler;H. Zeichhardt;R. Klopfleisch;W. Poller;C. Tschöpe;D. Lassner;H. Fechner;J. Kurreck
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作者：
E. A. Stein;S. Pinkert;P. Becher;Anja Geisler;H. Zeichhardt;R. Klopfleisch;W. Poller;C. Tschöpe;D. Lassner;H. Fechner;J. Kurreck
背景柯萨奇病毒B3(CVB3)是一种主要的心脏病原体，迄今为止尚无针对其的治疗方法。研究了由蛋白质病毒受体陷阱和基于 RNA 干扰的成分组成的联合治疗预防 CVB3 诱导的心肌炎的潜力。方法和结果 柯萨奇病毒腺病毒受体 (sCAR-Fc) 胞外结构域的可溶性变体由腺病毒载体表达，并由腺相关病毒 (AAV) 载体递送针对 CVB3 的 2 个短发夹 RNA (shRdRp2.4)。细胞培养实验揭示了联合应用的附加抗病毒活性。在 CVB3 诱导的小鼠心肌炎模型中，单独使用这两种成分可显着减少心脏中的炎症和病毒载量。该组合发挥了附加的抗病毒作用并减少了心脏病。血流动力学测量显示，CVB3 感染会导致心脏功能受损，表现为心输出量急剧减少以及收缩性和舒张性受损。 sCAR-Fc 或 shRdRp2.4 治疗显着改善了这些参数。重要的是，两种成分的结合可以进一步显着改善心脏功能。结论 sCAR-Fc 和 shRdRp2.4 的联合治疗在抑制 CVB3 诱导的心肌炎和预防心功能不全方面具有累加效应，并且比任何一种单一治疗均更有效。
BACKGROUND Coxsackievirus B3 (CVB3) is a major heart pathogen against which no therapy exists to date. The potential of a combination treatment consisting of a proteinaceous virus receptor trap and an RNA interference-based component to prevent CVB3-induced myocarditis was investigated. METHODS AND RESULTS A soluble variant of the extracellular domain of the coxsackievirus-adenovirus receptor (sCAR-Fc) was expressed from an adenoviral vector and 2 short hairpin RNAs (shRdRp2.4) directed against CVB3 were delivered by an adeno-associated virus (AAV) vector. Cell culture experiments revealed additive antiviral activity of the combined application. In a CVB3-induced mouse myocarditis model, both components applied individually significantly reduced inflammation and viral load in the heart. The combination exerted an additive antiviral effect and reduced heart pathology. Hemodynamic measurement revealed that infection with CVB3 resulted in impaired heart function, as illustrated by a drastically reduced cardiac output and impaired contractility and relaxation. Treatment with either sCAR-Fc or shRdRp2.4 significantly improved these parameters. Importantly, the combination of both components led to a further significant improvement of heart function. CONCLUSIONS Combination of sCAR-Fc and shRdRp2.4 exerted additive effects and was significantly more effective than either of the single treatments in inhibiting CVB3-induced myocarditis and preventing cardiac dysfunction.