Cardiac miR-19a/19b was induced and hijacked by CVB3 to facilitate virus replication via targeting viral genomic RdRp-encoding region
Cardiac miR-19a/19b was induced and hijacked by CVB3 to facilitate virus replication via targeting viral genomic RdRp-encoding region
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DOI：
10.1016/j.antiviral.2023.105702
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发表时间：
2023-08-21
影响因子：
7.6
通讯作者：
Xiong，Sidong
中科院分区：
文献类型：
--
作者：
Wu，Yingchun;Yue，Yan;Xiong，Sidong
柯萨奇病毒B3（CVB 3）是病毒性心肌炎的主要病原体之一，缺乏特异性抗病毒治疗方案。越来越多的证据表明miR-17-92簇在病毒感染和心血管疾病的发生和发展中起着重要作用，而其在CVB 3诱导的病毒性心肌炎中的作用尚不清楚。在这项研究中，我们发现miR-19 a和miR-19 b在CVB 3感染小鼠的心脏组织中显著上调，并对CVB 3的生物合成和复制产生显著的促进作用，其中miR-19 b的作用更为明显，通过靶向病毒RNA依赖性RNA聚合酶3D（RdRp，3Dpol）的编码区来增加病毒基因组RNA的稳定性。病毒3Dpol编码区中的同义突变使病毒促进作用无效，所述同义突变对应于miR-19 a和miR-19 b共享的种子序列。与此同时，miR-19 b治疗不仅显著抑制了感染细胞中的CVB 3复制和感染，而且还显示了CVB 3感染小鼠心脏病毒载量的显著降低，从而显著缓解了心肌炎。综上所述，我们的研究表明，CVB 3诱导的心肌miR-19 a/19 b通过促进病毒的生物合成和复制而促进病毒性心肌炎的发生，靶向miR-19 a/19 b可能成为CVB 3诱导的病毒性心肌炎的一个新的治疗靶点。
Coxsackievirus B3 (CVB3) is one of the major pathogens of viral myocarditis, lacking specific anti-virus therapeutic options. Increasing evidence has shown an important involvement of the miR-17-92 cluster both in virus infection and cardiovascular development and diseases, while its role in CVB3-induced viral myocarditis remains unclear. In this study, we found that miR-19a and miR-19b were significantly up-regulated in heart tissues of CVB3-infected mice and exerted a significant facilitatory impact on CVB3 biosynthesis and replication, with a more pronounced effect observed in miR-19b, by targeting the encoding region of viral RNA-dependent RNA polymerase 3D (RdRp, 3Dpol) to increase viral genomic RNA stability. The virus-promoting effects were nullified by the synonymous mutations in the viral 3Dpol-encoding region, which corresponded to the seed sequence shared by miR-19a and miR-19b. In parallel, treatment with miR-19b antagomir not only resulted in a noteworthy suppression of CVB3 replication and infection in infected cells, but also demonstrated a significant reduction in the cardiac viral load of CVB3-infected mice, resulting in a considerable alleviation of myocarditis. Collectively, our study showed that CVB3-induced cardiac miR-19a/19b contributed to viral myocarditis via facilitating virus biosynthesis and replication, and targeting miR-19a/19b might represent a novel therapeutic target for CVB3-induced viral myocarditis.