Advances in Microbiology
Vol. 08  No. 01 ( 2019 ), Article ID: 29182 , 7 pages
10.12677/AMB.2019.81003

Advances in Research on MicroRNAs Regulating Host Antiviral Innate Immunity

Tingting Han, Le Guo, Yuanying Shen

College of Basic Medicine, Dali University, Dali Yunnan

Received: Feb. 14th, 2019; accepted: Feb. 28th, 2019; published: Mar. 8th, 2019

ABSTRACT

MicroRNA (miRNA) is a kind of non-coding RNA with length of 19 - 24 nucleotides, which regulates the physiological processes of cells. Virus infection can induce the expression of some miRNAs in host cells. These miRNAs are involved in regulating the antiviral natural immune response of the host in turn, thereby enhancing the host's antiviral ability. Deeply exploring the natural immune process of host antiviral mediated by miRNAs has far-reaching significance for elucidating the pathogenesis of viruses and formulating new gene therapy strategies.

Keywords:MicroRNA, Antivirus, Natural Immunity, Gene Regulation

MicroRNAs调控宿主抗病毒天然免疫的 研究进展

韩婷婷,郭 乐,申元英

大理大学基础医学院,云南 大理

收稿日期:2019年2月14日;录用日期:2019年2月28日;发布日期:2019年3月8日

摘 要

MicroRNA (miRNA)是一类长度为19~24个核苷酸的非编码RNA,参与调控细胞的各生理过程。病毒感染宿主后能够诱导细胞内某些miRNAs的表达,这些miRNAs又反过来参与调控宿主的抗病毒天然免疫应答,进而增强宿主抗病毒能力。深入探究miRNAs介导的宿主抗病毒天然免疫过程,对于阐明病毒的致病机理和制定新的基因治疗策略具有深远的意义。

关键词 :MicroRNA,抗病毒,天然免疫,基因调控

Copyright © 2019 by authors and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 前言

病毒感染被视为现代人类健康的主要威胁,是当今社会突出的公共卫生问题。当病毒感染宿主细胞后,宿主会通过多种机制诱导免疫系统激活,其中天然免疫是宿主抗病毒的第一道防线,在抗病毒的过程中起到至关重要的作用。天然免疫系统通过细胞上的各种模式识别受体(pattern recognition receptors, PRRs)来识别病原体相关的模式分子(pathogen-associated molecular pattern, PAMP),触发信号分子,活化下游信号通路,促进炎性细胞因子和I/III型干扰素(Type I/III interferon, IFN-I/III)的产生 [1] [2] ,干扰病毒复制,诱导细胞RNA降解,最终导致感染细胞的凋亡 [3]。

MicroRNA (miRNA)是一类长度为19~24个核苷酸的非编码RNA,不参与编码蛋白质,而是通过基因转录后调控细胞的各生理过程。病毒感染宿主细胞后,可通过多种方式使宿主细胞免疫相关的miRNA表达谱发生变化,这些miRNA参与调控宿主的抗病毒天然免疫应答,进而增强宿主抗病毒能力。另外,有部分病毒也可以自身编码miRNA,对机体免疫应答和调控造成影响,并进而帮助病毒免疫逃逸或保护受感染细胞免于凋亡。本文就miRNAs调控宿主抗病毒天然免疫的机制及研究进展进行综述,为认识和开发新的抗病毒治疗方案提供新的研究方向和理论依据。

2. miRNA的形成及作用机制

MicroRNA (miRNA)是一类长度为19~24个核苷酸的非编码RNA,广泛存在于动植物细胞中,不参与编码蛋白质,而是通过基因转录后调控细胞的各生理过程,包括细胞的增殖、分化、凋亡和病毒感染等 [4] [5] [6] [7]。miRNA最早是由LeeRC等在1993年在秀丽隐杆线虫体内发现的,其编码22 nt的RNA片段可以靶向lin-14和lin-28基因,调控其表达 [8]。到目前为比,已有数以千计的miRNAs在动植物细胞中被发现,研究推测人类30%编码蛋白的基因也受到这些小的非编码RNA的调控 [9]。

miRNA的典型生物形成过程是细胞核内生物基因组由RNA聚合酶II (RNA-pol II)转录生成miRNA的初级前体(primary-miRNA, pri-miRNA)。该初级前体由微处理器(核酸酶Drosha及其辅助因子DGCR8)在核内加工后产生发夹结构前体(pre-miRNA)。该发夹结构前体由运输蛋白5 (Exportin-5)转运出细胞核 [10] [11]。在细胞质中,pre-miRNA被内切酶Dicer加工成成熟的miRNA双链体,大小约为21~23 nt。其中一条链装配核糖核蛋白(ribonucleo protein, RNP)形成RNA诱导沉默复合物(RNA induced silencing complex, RISC)。该复合物可通过miRNA种子区域与靶mRNA结合靶向介导转录后基因调控,另一条miRNA链则发生降解 [12] [13]。miRNA的调控作用取决于miRNA与靶基因序列的互补程度,若miRNA与靶基因完全互补配对,则mRNA被降解;若miRNA与靶基因部分互补,则miRNA会抑制mRNA的翻译。研究发现,植物的miRNA多与mRNA完全互补造成其降解,动物的miRNA多与mRNA部分互补抑制其翻译 [14]。

3. 宿主抗病毒天然免疫

天然免疫也叫先天免疫或固有免疫,是机体抵御病原体入侵的第一道防线。病毒感染宿主细胞后,天然免疫被激活,天然免疫细胞上的模式识别受体(pattern recognition receptors, PRRs)识别病原微生物上相对保守的相关分子模式(pathogen-associated molecular patterns, PAMPs)。宿主细胞的模式识别受体,Toll样受体(Toll-like receptors, TLRs)、维甲酸诱导基因工受体(RIG-I-like receptors, RLRs)以及胞浆DNA受体(cytoplasmic DNA sensors)等识别病毒相关的核酸成分。这些模式识别受体会通过TRIF、MAVS或STING等关键的接头蛋白来活化TBK1,从而激活转录因子IRF3来诱导I/III型干扰素的表达 [15] [16] [17]。干扰素在宿主细胞抗病毒天然中发挥重要的作用,但干扰素本身并不具有杀伤或者抑制病毒复制的功能,而是通过与细胞表面的相应受体结合,激活下游的JAK/STAT1信号通路,从而诱导多种干扰素诱导基因表达,诱导细胞产生抗病毒蛋白,在病毒复制的不同阶段发挥抗病毒天然免疫作用 [18] [19]。

4. miRNA调控宿主抗病毒天然免疫应答

病毒感染宿主细胞后,引起宿主细胞内miRNA表达变化,部分miRNA参与调控宿主抗病毒天然免疫应答,增强宿主抗病毒能力。随着对miRNA的深入研究,宿主细胞内miRNA调控天然免疫应答的机制也有了更深入的认识。宿主细胞内miRNA主要是从以下三个方面参与调控宿主抗病毒天然免疫应答,靶向调控细胞受体、靶向调控细胞信号通路以及靶向调控与病毒复制有关的细胞因子(见图1)。

注:DENV (登革热病毒);EV71 (肠道病毒EV71);HCV (丙型肝炎病毒);HIV-1 (人类免疫缺陷病毒);JEV (日本脑炎病毒);Poliovirus (脊髓灰质炎病毒);PRRSV (猪繁殖和呼吸障碍综合症病毒);WNV (西尼罗河病毒)。

Figure 1. The innate immune mechanism of microRNAs regulating host antiviral immunity

图1. miRNA调控宿主抗病毒天然免疫机制

4.1. miRNA靶向调控细胞受体

病毒侵染宿主细胞的第一步是通过表达病毒受体进入特定细胞,miRNA通过调控宿主细胞受体的表达,可以抑制病毒的侵染。Lodge等 [20] 发现人类免疫缺陷病毒(HIV-1)受体CD4蛋白受miR-221和miR-222的调控。在研究中发现,这两种miRNA在未被感染的巨噬细胞中高表达,而在已经被感染的巨噬细胞中表达量下降。并证实miR-221和miR-222可通过下调巨噬细胞CD4蛋白的表达来限制HIV-1进入巨噬细胞,从而起到抵抗病毒侵染的效果。猪繁殖和呼吸障碍综合症病毒(PRRSV)通常感染巨噬细胞和树突细胞,并且在较小程度上感染单核细胞,这种趋向性是由PRRSV受体CD163在这些细胞表面的表达程度决定的 [21]。Gao等 [22] 研究证明miR-181可以通过靶向CD163 mRNA的3'非翻译区域(UTR)下调血液单核细胞和猪肺泡巨噬细胞(PAMs)表面PRRSV受体CD163的表达量,从而抑制PRRSV进入细胞,起到抗病毒感染的作用。同时该课题组也证明,miR-181可以通过直接靶向PRRSV的基因组RNA来抑制其的复制 [23]。因此miR-181对该病毒发挥双重作用,既靶向病毒基因组又通过调节CD163间接调控病毒的入侵。

4.2. miRNA靶向调控干扰素信号通路

干扰素在宿主抗病毒天然免疫应答中发挥重要作用。miRNA通过靶向调控干扰素信号通路中的相关蛋白,从而增强干扰素介导的抗病毒能力。Smith等 [24] 证实miR-34a是黄病毒复制的有效抑制剂,通过对比miR-34a转染进细胞后对黄病毒复制生长曲线的影响,进一步证实miR-34a对登革热病毒(DENV)、西尼罗河病毒(WNV)和日本脑炎病毒(JEV)的抑制作用。实验表明miR-34a是基于天然免疫途径,通过抑制Wnt/β-catenin信号通路的传导,增强IFN-I对病毒感染细胞后的反应速度,从而增强宿主抗病毒天然免疫能力。丙型肝炎病毒(HCV)感染是慢性肝病的主要原因,虽然正在开发新的抗HCV药物,但目前的标准疗法主要由干扰素(IFN)组成。GangXu等 [25] 研究发现miRNA-221具有增强IFN-I抗HCV的作用。其机制是miRNA-221靶向下调细胞内SOCS-1和SOCS-3的表达量,SOCS蛋白是多个干扰素信号通路的负调节剂 [26] ,因此增强了IFN-I的抗病毒效应并且抑制HCV复制。Yoshikawa等 [27] 研究发现,HCV感染时miR-122也参与调控干扰素信号通路,通过沉默miR-122可下调SOCS3的表达,增强IFN诱导的干扰素激活反应元件(ISRF)的活性,从而抑制HCV的复制。

4.3. miRNA靶向调控病毒复制相关细胞因子

病毒复制过程涉及各种相关细胞因子,因此部分miRNA靶向调控与病毒复制相关的细胞因子,抑制病毒的复制。Diosa-Toro等 [28] 用DENV感染人原代巨噬细胞,筛选了巨噬细胞miRNA表达谱,确定miR-3614-5p抑制DENV在人原代巨噬细胞中复制的作用。用DENV感染的巨噬细胞后miR-3614-5p在DENV阴性细胞中上调,且miR-3614-5p的过表达可以使DENV的感染性降低。然而在DENV感染的细胞中发现上调的miR-3614-5p并不能控制感染性病毒颗粒的产生。通过液相色谱和蛋白质印迹鉴定miR-3614-5p的细胞靶点,发现ADAR1为miR-3614-5p的靶点之一。ADAR1是一种促进病毒复制的蛋白质,miR-3614-5p通过下调ADAR1的表达量,从而降低DENV的感染性。Tang等 [29] 发现肠道病毒EV71感染细胞后,细胞中miR-197的表达量会下调。体外细胞实验证实,miR-197的过表达会抑制EV71的复制,而抑制miR-197表达后EV71复制水平将显著升高(p < 0.05)。随后他们利用蛋白质组学的方法证实RAN因子是miR-197的一个细胞靶点,RAN是与病毒复制相关蛋白3D和3DC进入细胞核的重要调控因子,从而起到抑制病毒复制的作用。Chen等 [30] 发现JEV感染下调内源性细胞miR-33a的表达,用miR-33a模拟物人工转染导致病毒复制显着减少,表明miR-33a是JEV复制的负调控因子。并且采用双荧光素酶基因测定法将真核翻译延伸因子1A1 (EEF1A1)鉴定为miR-33a的靶基因之一。进一步研究证明EEF1A1可以与JEV蛋白NS3和NS5相互作用,通过这种相互作用,EEF1A1可以稳定病毒复制酶复合物的组分,从而促进JEV感染期间的病毒复制。这些结果表明miR-33a在JEV感染期间下调,其通过靶向EEF1A1因子,降低其与JEV的NS3和NS5的相互作用,起到抑制病毒复制的作用。在脊髓灰质炎病毒感染的情况下,Shim等 [31] 通过高通量过表达筛选,将miR-555鉴定为具有抗病毒特性的miRNA,并显示hnRNP C为该miRNA的靶点,而hnRNP C是病毒复制机制中的重要蛋白。因此miR-555表达量上调,靶向降低hnRNP C蛋白的表达量,抑制病毒的复制。

5. 展望

本文只对病毒感染宿主后,一些miRNA正向调控宿主抗病毒天然免疫的机制进行了综述。然而在病毒感染宿主后,并非所有miRNA表达量的变化都是对宿主有利的,宿主内的某些miRNA也会负向调控宿主抗病毒天然免疫的功能,干扰宿主的抗病毒天然免疫反应或促进病毒复制,使病毒更易感染细胞。例如Rosenberger等 [32] 研究发现,miR-144是流感病毒、脑心肌炎病毒(EMCV)和水疱性口炎病毒(VSV)这三种RNA病毒感染宿主后的负调控因子,miR-144转录后抑制TRAF6表达水平,从而下调IRF7介导的免疫应答,削弱宿主的抗病毒天然免疫能力。Jennifer等 [33] 研究发现HIV-1感染后,结肠粘膜中miR-26a和miR-29a的表达下调,且这两种miRNA直接作用于IL-6和STAT3,能抑制IL-6/STAT3信号通路,这可能导致感染期间炎症增加,从而利于HIV-1的复制。Bibhabasu Hazra等 [34] 发现JEV感染诱导miR-301a的表达上调,miR-301a能抑制I型IFN的产生,削弱宿主的抗病毒天然免疫,使得病毒的复制增加。

miRNA是近年来研究的热点领域,关于miRNA对宿主抗病毒天然免疫应答的调控作用逐渐受到人们的关注。对于miRNA在病毒感染宿主后调控天然免疫应答机制研究不仅揭示miRNA在免疫应答中的相关作用,也为制定新型基因治疗方案和抗病毒疫苗的制备提供了理论依据。使用miRNA作为工具来修饰基因表达对于治疗人类疾病具有较好的前景 [35]。在抗病毒治疗中,miRNA显示出低免疫原性,可在动物模型体内抑制或过表达特定的miRNA进行临床试验验证其功能 [36] [37]。目前关于miRNA抗病毒的相关治疗研究已在进行中,并取得了一定进展 [38]。随着miRNA调控抗病毒免疫应答机制研究的不断深入,有助于全面了解宿主抗病毒天然免疫机制,并使得基于miRNA转录后基因沉默用于治疗病毒感染成为可能。

文章引用

韩婷婷,郭 乐,申元英. MicroRNAs调控宿主抗病毒天然免疫的研究进展
Advances in Research on MicroRNAs Regulating Host Antiviral Innate Immunity[J]. 微生物前沿, 2019, 08(01): 15-21. https://doi.org/10.12677/AMB.2019.81003

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