Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
J Virol. 2020 Jun 16;94(13). doi: 10.1128/JVI.00454-20.
The small messenger RNA (SmRNA) of the (ANDV), a rodent-borne member of the family of viruses of the order, encodes a multifunctional nucleocapsid (N) protein and for a nonstructural (NSs) protein of unknown function. We have previously shown the expression of the ANDV-NSs, but only in infected cell cultures. In this study, we extend our early findings by confirming the expression of the ANDV-NSs protein in the lungs of experimentally infected golden Syrian hamsters. Next, we show, using a virus-free system, that the ANDV-NSs protein antagonizes the type I interferon (IFN) induction pathway by suppressing signals downstream of the melanoma differentiation-associated protein 5 (MDA5) and the retinoic acid-inducible gene 1 (RIG-I) and upstream of TBK1. Consistent with this observation, the ANDV-NSs protein antagonized mitochondrial antiviral-signaling protein (MAVS)-induced IFN-β, NF-κB, IFN-regulatory factor 3 (IRF3), and IFN-sensitive response element (ISRE) promoter activity. Results demonstrate that ANDV-NSs binds to MAVS in cells without disrupting the MAVS-TBK-1 interaction. However, in the presence of the ANDV-NSs ubiquitination of MAVS is reduced. In summary, this study provides evidence showing that the ANDV-NSs protein acts as an antagonist of the cellular innate immune system by suppressing MAVS downstream signaling by a yet not fully understand mechanism. Our findings reveal new insights into the molecular regulation of the hosts' innate immune response by the Andes orthohantavirus. (ANDV) is endemic in Argentina and Chile and is the primary etiological agent of hantavirus cardiopulmonary syndrome (HCPS) in South America. ANDV is distinguished from other hantaviruses by its unique ability to spread from person to person. In a previous report, we identified a novel ANDV protein, ANDV-NSs. Until now, ANDV-NSs had no known function. In this new study, we established that ANDV-NSs acts as an antagonist of cellular innate immunity, the first line of defense against invading pathogens, hindering the cellular antiviral response during infection. This study provides novel insights into the mechanisms used by ANDV to establish its infection.
小型信使 RNA（SmRNA）的 （ANDV），一种啮齿动物传播的病毒家族的成员，病毒的 顺序，编码一种多功能核衣壳（N）蛋白和一个非结构（NSs）蛋白，其功能未知。我们之前已经表明 ANDV-NSs 的表达，但仅在感染的细胞培养物中。在这项研究中，我们通过证实实验感染的金黄地鼠肺中 ANDV-NSs 蛋白的表达来扩展我们早期的发现。接下来，我们使用无病毒系统表明，ANDV-NSs 蛋白通过抑制黑色素瘤分化相关蛋白 5（MDA5）和视黄酸诱导基因 1（RIG-I）下游以及 TBK1 上游的信号来拮抗 I 型干扰素（IFN）诱导途径。与这一观察结果一致，ANDV-NSs 蛋白拮抗线粒体抗病毒信号蛋白（MAVS）诱导的 IFN-β、NF-κB、干扰素调节因子 3（IRF3）和 IFN 敏感反应元件（ISRE）启动子活性。结果表明，ANDV-NSs 蛋白在不破坏 MAVS-TBK-1 相互作用的情况下与 MAVS 结合在细胞中。然而，在存在 ANDV-NSs 的情况下，MAVS 的泛素化减少。总之，这项研究提供了证据，表明 ANDV-NSs 蛋白通过抑制 MAVS 下游信号转导，充当细胞固有免疫系统的拮抗剂，通过一种尚未完全了解的机制。我们的发现揭示了安第斯 orthohantavirus 对宿主固有免疫反应的分子调控的新见解。（ANDV）在阿根廷和智利流行，是南美洲汉坦病毒心肺综合征（HCPS）的主要病原体。与其他汉坦病毒不同，ANDV 具有独特的在人与人之间传播的能力。在之前的一份报告中，我们鉴定了一种新型的 ANDV 蛋白，ANDV-NSs。到目前为止，ANDV-NSs 还没有已知的功能。在这项新的研究中，我们确定 ANDV-NSs 作为细胞固有免疫的拮抗剂，固有免疫是抵御入侵病原体的第一道防线，在感染过程中阻碍细胞抗病毒反应。这项研究提供了新的见解，了解 ANDV 用来建立其感染的机制。
