State Key Laboratory of Virology, Institute of Medical Virology, School of Basic Medical Sciences and Department of Infectious Diseases, Renmin Hospital, Wuhan University, Wuhan, China.
Department of Microbiology, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning, China.
Front Cell Infect Microbiol. 2020 Mar 13;10:97. doi: 10.3389/fcimb.2020.00097. eCollection 2020.
Hantaan virus (HTNV), a Hantavirus serotype that is prevalent in Asia, causes hemorrhagic fever with renal syndrome (HFRS) with high mortality in human race. However, the pathogenesis of HTNV infection remains elusive. Circular RNAs (circRNAs), a new type of non-coding RNAs, play a crucial role in various pathogenic processes. Nevertheless, circRNA expression profiles and their effects on pathogenesis of HTNV infection are still completely unknown. In the present study, RNA sequencing was performed to analyze the circRNA, microRNA (miRNA), and mRNA expression profiles in HTNV-infected and mock-infected human umbilical vein endothelial cells (HUVECs). A total of 70 circRNAs, 66 miRNAs, and 788 mRNAs were differently expressed. Several differentially expressed RNAs were validated by RT-qPCR. Moreover, we verified that some differentially expressed RNAs, such as circ_0000479, miR-149-5p, miR-330-5p, miR-411-3p, RIG-I, CMPK2, PARP10, and GBP1, promoted or inhibited HTNV replication. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis demonstrated that the host genes of differentially expressed circRNAs were principally involved in the innate immune response, the type I interferon (IFN) signaling pathway, and the cytokine-mediated signaling pathway. Additionally, the circRNA-miRNA-mRNA regulatory network was integrally analyzed. The data showed that there were many circRNA-miRNA-mRNA interactions in HTNV infection. By dual-luciferase reporter assay, we confirmed that circ_0000479 indirectly regulated RIG-I expression by sponging miR-149-5p, hampering viral replication. This study for the first time presents a comprehensive overview of circRNAs induced by HTNV and reveals that a network of enriched circRNAs and circRNA-associated competitive endogenous RNAs (ceRNAs) is involved in the regulation of HTNV infection, thus offering new insight into the mechanisms underlying HTNV-host interaction.
汉坦病毒（HTNV）是一种在亚洲流行的汉坦病毒血清型，可导致人类出血热伴肾综合征（HFRS），死亡率很高。然而，HTNV 感染的发病机制仍不清楚。环状 RNA（circRNA）是一种新型的非编码 RNA，在各种致病过程中发挥着关键作用。然而，circRNA 的表达谱及其对 HTNV 感染发病机制的影响仍完全未知。在本研究中，进行了 RNA 测序，以分析 HTNV 感染和模拟感染的人脐静脉内皮细胞（HUVEC）中的 circRNA、microRNA（miRNA）和 mRNA 表达谱。共有 70 个 circRNA、66 个 miRNA 和 788 个 mRNA 表达水平差异。通过 RT-qPCR 验证了一些差异表达的 RNA。此外，我们验证了一些差异表达的 RNA，如 circ_0000479、miR-149-5p、miR-330-5p、miR-411-3p、RIG-I、CMPK2、PARP10 和 GBP1，促进或抑制 HTNV 复制。基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析表明，差异表达 circRNA 的宿主基因主要参与固有免疫反应、I 型干扰素（IFN）信号通路和细胞因子介导的信号通路。此外，还综合分析了 circRNA-miRNA-mRNA 调控网络。数据表明，在 HTNV 感染中存在许多 circRNA-miRNA-mRNA 相互作用。通过双荧光素酶报告基因实验，我们证实 circ_0000479 通过海绵吸附 miR-149-5p 间接调节 RIG-I 的表达，从而抑制病毒复制。本研究首次全面展示了 HTNV 诱导的 circRNAs，并揭示了富含 circRNAs 和 circRNA 相关竞争性内源性 RNA（ceRNA）的网络参与了 HTNV 感染的调控，从而为 HTNV-宿主相互作用的机制提供了新的见解。
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