A prenylated dsRNA sensor protects against severe COVID-19.
A prenylated dsRNA sensor protects against severe COVID-19.
复制标题
异丙基双链RNA传感器可预防严重的新冠肺炎。
DOI：
10.1126/science.abj3624
复制
发表时间：
2021-10-29
期刊：
影响因子：
--
通讯作者：
Wilson SJ
中科院分区：
文献类型：
--
作者：
Wickenhagen A;Sugrue E;Lytras S;Kuchi S;Noerenberg M;Turnbull ML;Loney C;Herder V;Allan J;Jarmson I;Cameron-Ruiz N;Varjak M;Pinto RM;Lee JY;Iselin L;Palmalux N;Stewart DG;Swingler S;Greenwood EJD;Crozier TWM;Gu Q;Davies EL;Clohisey S;Wang B;Trindade Maranhão Costa F;Freire Santana M;de Lima Ferreira LC;Murphy L;Fawkes A;Meynert A;Grimes G;ISARIC4C Investigators;Da Silva Filho JL;Marti M;Hughes J;Stanton RJ;Wang ECY;Ho A;Davis I;Jarrett RF;Castello A;Robertson DL;Semple MG;Openshaw PJM;Palmarini M;Lehner PJ;Baillie JK;Rihn SJ;Wilson SJ
COVID-19 的异质性使得预测个体感染过程具有挑战性。病毒感染后，干扰素 (IFN) 会产生细胞防御的初始信号。 Wickenhagen 等人知道 IFN 信号传导缺陷与更严重的 COVID-19 相关。对人肺细胞使用 IFN 刺激的基因表达筛选，从中鉴定出 2'-5'-寡腺苷酸合成酶 1 (OAS1) 的基因（参见 Schoggins 的观点）。 OAS1 刺激 RNase L 以惊人的特异性抑制病毒，针对病毒复制的膜细胞器。在大多数哺乳动物中，OAS1 通过异戊二烯基团附着在膜上。然而，数十亿人不具有异戊二烯化的 OAS1 单倍型，其中包括许多患有严重 COVID-19 的人。由于古老的逆转录转座事件，马蹄蝠也是如此，马蹄蝠是β冠状病毒的多产来源。 —CA 人类干扰素系统中激活 SARS-CoV-2 细胞防御的一种成分在大部分人身上似乎存在缺陷。干扰素 (IFN) 是快速部署以应对入侵病原体的细胞因子。通过启动刺激数百个基因表达的信号级联反应，干扰素在宿主细胞中产生抗病毒状态。由于 IFN 严重影响 COVID-19 的结果，并且抗病毒状态可抑制严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的复制，因此了解 IFN 刺激基因 (ISG) 编码的个体抗病毒效应物如何抑制 SARS-CoV-2 非常重要。我们假设 IFN 刺激的抗病毒效应物可以抑制 SARS-CoV-2，而编码这些防御的基因座的变异是为什么有些人更容易感染严重的 COVID-19 的原因。我们使用阵列 ISG 表达筛选来揭示 2′-5′-寡腺苷酸合成酶 1 (OAS1) 在不同情况下一致抑制 SARS-CoV-2。使用 CRISPR-Cas9，我们发现内源性 OAS1 通过识别短链双链 RNA (dsRNA) 并激活 RNase L，对抗病毒状态做出了重大贡献。我们对 OAS1 与 SARS-CoV-2 病毒 RNA 结合的位置进行了全局绘制，发现 OAS1 结合具有非常特异性，在构成主要病毒的 SARS-CoV-2 5'-非翻译区 (UTR) 中有两个保守的茎环目标。在死于 COVID-19 的个体的感染部位很容易检测到 OAS1 表达，并且已知特定的 OAS1 等位基因与感染和严重疾病的易感性改变有关。此前曾有报道称，OAS1 (Rs10774671) 中含有常见剪接受体单核苷酸多态性的等位基因与较轻的 COVID-19 相关。我们确定，在该位置至少有一个带有 G 等位基因的人可以表达 OAS1 (p46) 的异戊二烯化形式，而其他人则不能。使用一系列突变体，我们发现 C 端异戊二烯化对于 OAS1 启动对 SARS-CoV-2 的阻断是必要的。此外，共聚焦显微镜显示，异戊二烯化将 OAS1 靶向富含病毒 dsRNA 的核周结构，而非异戊二烯化 OAS1 广泛定位，无法启动可检测的对 SARS-CoV-2 复制的阻断。认识到异戊二烯化对于 OAS1 介导的 SARS-CoV-2 感知至关重要，这使我们能够检查受感染患者的转录组，并研究异戊二烯化 OAS1 的表达与 SARS-CoV-2 疾病进展之间是否存在联系。对 499 名住院 COVID-19 患者的 OAS1 转录本的分析显示，表达异戊二烯化 OAS1 与预防严重 COVID-19 相关。由于异戊二烯化的 OAS1 在人类病例中非常重要，因此我们想确定马蹄蝠（SARS-CoV-2 的可能来源）是否具有相同的防御能力。当我们检查异戊二烯化信号所在的基因组区域时，长末端重复序列的逆转座消除了该信号，从而阻止了这些蝙蝠中异戊二烯化抗冠状病毒 OAS1 的表达。 C 端异戊二烯化将 OAS1 靶向富含病毒 dsRNA 的细胞内位点，这些位点可能是 SARS-CoV-2 复制细胞器。一旦到达正确的位置，OAS1 就会与 SARS-CoV-2 5'-UTR 中的 dsRNA 结构结合，并启动对 SARS-CoV-2 复制的有效阻断。因此，OAS1 的正确靶向以及随后对 SARS-CoV-2 的抑制可能支持 Rs10774671 处含有 G 的等位基因与降低对 COVID-19 感染和严重疾病的易感性的遗传关联。此外，马蹄蝠明显缺乏这种抗病毒防御能力，这可能解释了为什么 SARS-CoV-2 对人类的这种防御能力如此敏感。一种常见的基因多态性决定了人们是否产生膜相关形式的 OAS1（一种 dsRNA 传感器）。异戊二烯化将 OAS1 靶向富含病毒 dsRNA 的位点。一旦到达正确的位置，OAS1 就会感知 SARS-CoV-2 5'-UTR 中的 dsRNA 结构，并启动对 SARS-CoV-2 复制的有效阻断。 OAS1 基于 PDB ID 4IG8。遗传因素可能会影响 COVID-19 的严重程度，但支持遗传关联的分子解释通常尚不清楚。细胞内抗病毒防御可以抑制病毒的复制并减轻疾病的严重程度。为了更好地了解与 COVID-19 相关的抗病毒防御，我们使用干扰素刺激基因 (ISG) 表达筛选来揭示 2′-5′-寡腺苷酸合成酶 1 (OAS1) 通过核糖核酸酶 L 有效抑制严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)。我们发现，常见的剪接受体单核苷酸多态性 (Rs10774671) 控制着患者是否表达异戊二烯化 OAS1 亚型（即 SARS-CoV-2 RNA 的膜相关和正义特异性区域），或者是否仅表达胞质非异戊二烯化 OAS1，而不能有效检测 SARS-CoV-2。在住院患者中，异戊二烯化 OAS1 的表达与预防严重 COVID-19 相关，表明这种抗病毒防御是保护性抗病毒反应的主要组成部分。
The heterogeneity of COVID-19 makes it challenging to predict the course of infection in an individual. Upon virus infection, interferons (IFNs) generate the initial signals for cellular defenses. Knowing that defects in IFN signaling are associated with more severe COVID-19, Wickenhagen et al. used IFN-stimulated gene expression screening on human lung cells from which they identified a gene for 2′-5′-oligoadenylate synthetase 1 (OAS1) (see the Perspective by Schoggins). OAS1 stimulates RNase L to inhibit the virus with a surprising degree of specificity, targeting the membranous organelles in which it replicates. In most mammals, OAS1 is attached to membranes by a prenyl group. However, billions of humans do not have the prenylated OAS1 haplotype, including many experiencing severe COVID-19. The same is true for horseshoe bats, prolific sources of betacoronaviruses, because of an ancient retrotransposition event. —CA A component of the human interferon system that activates SARS-CoV-2 cellular defenses appears to be defective in a large proportion of humans. Interferons (IFNs) are cytokines that are rapidly deployed in response to invading pathogens. By initiating a signaling cascade that stimulates the expression of hundreds of genes, IFNs create an antiviral state in host cells. Because IFNs heavily influence COVID-19 outcomes, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication can be inhibited by the antiviral state, it is important to understand how the individual antiviral effectors encoded by IFN-stimulated genes (ISGs) inhibit SARS-CoV-2. We hypothesized that IFN-stimulated antiviral effectors can inhibit SARS-CoV-2, and that variation at the loci encoding these defenses underlies why some people are more susceptible to severe COVID-19. We used arrayed ISG expression screening to reveal that 2′-5′-oligoadenylate synthetase 1 (OAS1) consistently inhibited SARS-CoV-2 in different contexts. Using CRISPR-Cas9, we found that endogenous OAS1 makes a substantial contribution to the antiviral state by recognizing short stretches of double-stranded RNA (dsRNA) and activating RNase L. We globally mapped where OAS1 binds to SARS-CoV-2 viral RNAs and found that OAS1 binding is remarkably specific, with two conserved stem loops in the SARS-CoV-2 5′-untranslated region (UTR) constituting the principal viral target. OAS1 expression was readily detectable at the sites of infection in individuals who died of COVID-19, and specific OAS1 alleles are known to be associated with altered susceptibility to infection and severe disease. It had previously been reported that alleles containing a common splice-acceptor single nucleotide polymorphism in OAS1 (Rs10774671) were associated with less severe COVID-19. We determined that people with at least one allele with a G at this position could express a prenylated form of OAS1 (p46), whereas other individuals could not. Using a series of mutants, we found that C-terminal prenylation was necessary for OAS1 to initiate a block to SARS-CoV-2. Furthermore, confocal microscopy revealed that prenylation targeted OAS1 to perinuclear structures rich in viral dsRNA, whereas non-prenylated OAS1 was diffusely localized and unable to initiate a detectable block to SARS-CoV-2 replication. The realization that prenylation is essential for OAS1-mediated sensing of SARS-CoV-2 allowed us to examine the transcriptome of infected patients and investigate whether there was a link between the expression of prenylated OAS1 and SARS-CoV-2 disease progression. Analysis of the OAS1 transcripts from 499 hospitalized COVID-19 patients revealed that expressing prenylated OAS1 was associated with protection from severe COVID-19. Because prenylated OAS1 was so important in human cases, we wanted to determine whether horseshoe bats, the likely source of SARS-CoV-2, possessed the same defense. When we examined the genomic region where the prenylation signal should reside, retrotransposition of a long terminal repeat sequence had ablated this signal, preventing the expression of prenylated anti-CoV OAS1 in these bats. C-terminal prenylation targets OAS1 to intracellular sites rich in viral dsRNA, which are likely the SARS-CoV-2 replicative organelles. Once in the right place, OAS1 binds to dsRNA structures in the SARS-CoV-2 5′-UTR and initiates a potent block to SARS-CoV-2 replication. Thus, the correct targeting of OAS1 and the subsequent inhibition of SARS-CoV-2 likely underpins the genetic association of alleles containing a G at Rs10774671 with reduced susceptibility to infection and severe disease in COVID-19. Moreover, the conspicuous absence of this antiviral defense in horseshoe bats potentially explains why SARS-CoV-2 is so sensitive to this defense in humans. A common genetic polymorphism determines whether people make a membrane-associated form of OAS1, a dsRNA sensor. Prenylation targets OAS1 to sites rich in viral dsRNA. Once in the correct place, OAS1 senses dsRNA structures in the SARS-CoV-2 5′-UTR and initiates a potent block to SARS-CoV-2 replication. OAS1 based on PDB ID 4IG8. Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that 2′-5′-oligoadenylate synthetase 1 (OAS1), through ribonuclease L, potently inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We show that a common splice-acceptor single-nucleotide polymorphism (Rs10774671) governs whether patients express prenylated OAS1 isoforms that are membrane-associated and sense-specific regions of SARS-CoV-2 RNAs or if they only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. In hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting that this antiviral defense is a major component of a protective antiviral response.
登录
查看更多内容
影响因子：
28.3
作者：
Doyle, Tomas;Moncorge, Olivier;Malim, Michael H.
通讯作者：
Malim, Michael H.
危及生命的Covid-19患者中针对I型IFN的自身抗体。
DOI：
10.1126/science.abd4585
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bastard P;Rosen LB;Zhang Q;Michailidis E;Hoffmann HH;Zhang Y;Dorgham K;Philippot Q;Rosain J;Béziat V;Manry J;Shaw E;Haljasmägi L;Peterson P;Lorenzo L;Bizien L;Trouillet-Assant S;Dobbs K;de Jesus AA;Belot A;Kallaste A;Catherinot E;Tandjaoui-Lambiotte Y;Le Pen J;Kerner G;Bigio B;Seeleuthner Y;Yang R;Bolze A;Spaan AN;Delmonte OM;Abers MS;Aiuti A;Casari G;Lampasona V;Piemonti L;Ciceri F;Bilguvar K;Lifton RP;Vasse M;Smadja DM;Migaud M;Hadjadj J;Terrier B;Duffy D;Quintana-Murci L;van de Beek D;Roussel L;Vinh DC;Tangye SG;Haerynck F;Dalmau D;Martinez-Picado J;Brodin P;Nussenzweig MC;Boisson-Dupuis S;Rodríguez-Gallego C;Vogt G;Mogensen TH;Oler AJ;Gu J;Burbelo PD;Cohen JI;Biondi A;Bettini LR;D'Angio M;Bonfanti P;Rossignol P;Mayaux J;Rieux-Laucat F;Husebye ES;Fusco F;Ursini MV;Imberti L;Sottini A;Paghera S;Quiros-Roldan E;Rossi C;Castagnoli R;Montagna D;Licari A;Marseglia GL;Duval X;Ghosn J;HGID Lab;NIAID-USUHS Immune Response to COVID Group;COVID Clinicians;COVID-STORM Clinicians;Imagine COVID Group;French COVID Cohort Study Group;Milieu Intérieur Consortium;CoV-Contact Cohort;Amsterdam UMC Covid-19 Biobank;COVID Human Genetic Effort;Tsang JS;Goldbach-Mansky R;Kisand K;Lionakis MS;Puel A;Zhang SY;Holland SM;Gorochov G;Jouanguy E;Rice CM;Cobat A;Notarangelo LD;Abel L;Su HC;Casanova JL
通讯作者：
Casanova JL
影响因子：
6.4
作者：
Gusho E;Zhang R;Jha BK;Thornbrough JM;Dong B;Gaughan C;Elliott R;Weiss SR;Silverman RH
通讯作者：
Silverman RH
抗病毒 2′,5′-寡腺苷酸合成酶（2′5′AS）酶活性的变化受 OAS1 基因中剪接接受位点单核苷酸多态性的控制
影响因子：
9.8
作者：
Bonnevie-Nielsen, V;Field, LL;Pociot, F
通讯作者：
Pociot, F
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS