Burke J Daniel, Sonenberg Nahum, Platanias Leonidas C, Fish Eleanor N
Toronto General Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, ON, Canada.
Antivir Ther. 2011;16(4):577-84. doi: 10.3851/IMP1752.
Viral myocarditis is most frequently associated with infection by Coxsackievirus B3 (CVB3). Interferon (IFN)-β therapy has been studied and could reduce virally induced tissue damage and improve heart function.
In the present study we have investigated the role of translational suppression in the context of an IFN-α/β-mediated antiviral immune response to CVB3 infection. Specifically, we examined the effects of IFN-α/β treatment of CVB3-infected mouse embryonic fibroblast cells and splenocytes lacking eukaryotic initiation factor 4E binding protein-1 (4E-BP1), a suppressor of 5'-capped mRNA translation. Extending these in vitro studies, we examined the effects of CVB3 infection and IFN-β treatment in 4E-BP1(-/-) mice.
Our data show that 4E-BP1(-/-) cells are more -sensitive to the antiviral effects of IFN-α4 and IFN-β treatment than 4E-BP1(+/+) cells when infected with CVB3. Similarly, 4E-BP1(-/-) mice are more sensitive to treatment with IFN-β, exhibiting lower viral titres in heart tissue than 4E-BP1(+/+) mice during the course of infection. Additionally, we demonstrate that treatment with IFN-β reduces inflammatory infiltrates into the hearts of infected mice.
These data identify 4E-BP1 as a novel drug target to augment responsiveness to IFN-β therapy in CVB3-induced myocarditis.
病毒性心肌炎最常与柯萨奇病毒B3（CVB3）感染相关。干扰素（IFN）-β疗法已被研究，可减少病毒诱导的组织损伤并改善心脏功能。
在本研究中，我们研究了翻译抑制在IFN-α/β介导的针对CVB3感染的抗病毒免疫反应中的作用。具体而言，我们检测了IFN-α/β处理CVB3感染的小鼠胚胎成纤维细胞和缺乏真核起始因子4E结合蛋白-1（4E-BP1，一种5'-帽状mRNA翻译抑制剂）的脾细胞的效果。扩展这些体外研究，我们检测了CVB3感染和IFN-β处理对4E-BP1基因敲除小鼠的影响。
我们的数据表明，感染CVB3时，4E-BP1基因敲除细胞比4E-BP1基因野生型细胞对IFN-α4和IFN-β处理的抗病毒作用更敏感。同样，4E-BP1基因敲除小鼠对IFN-β治疗更敏感，在感染过程中，其心脏组织中的病毒滴度低于4E-BP1基因野生型小鼠。此外，我们证明IFN-β处理可减少感染小鼠心脏中的炎性浸润。
这些数据确定4E-BP1是增强CVB3诱导的心肌炎对IFN-β治疗反应性的新药物靶点。
