Betacoronaviruses: activation and antagonism of host innate immune responses

β冠状病毒：宿主先天免疫反应的激活和拮抗

• 批准号: 10735058
• 负责人: Susan R Weiss
• 金额: $ 54.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-24 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735058
• 关键词: 2019-nCoV; Biology; COVID-19 pneumonia; Cell Death; Cells; Coronavirus; Cyclic AMP-Dependent Protein Kinases; Data; Disease; Disease Outbreaks; Double-Stranded RNA; Endoribonucleases; Feedback; Future; Genes; Genome; Goals; Human; Immune; Immune response; In Vitro; Individual; Infection; Inflammation; Inflammatory; Innate Immune Response; Interferons; Ligase; Lung; Messenger RNA; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Mus; Outcome; Pathogenicity; Pathway interactions; Pattern recognition receptor; Peptide Initiation Factors; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Pneumonia; Production; Protein Biosynthesis; Protein Dephosphorylation; Proteins; RNA; Respiratory Disease; Ribonucleases; Role; SARS coronavirus; SARS-CoV-2 infection; Sarbecovirus; Scheme; Signal Transduction; Structure; System; Therapeutic; Upper respiratory tract; Viral; Viral Genome; Viral Proteins; Virus; Virus Replication; Work; antagonist; attenuation; betacoronavirus; biological adaptation to stress; cell injury; combat; coronavirus treatment; endoplasmic reticulum stress; experience; human coronavirus; in vivo; interest; lung injury; mouse model; mutant; novel therapeutic intervention; oligoadenylate; phosphoric diester hydrolase; prevent; protein activation; protein kinase R; replicase; respiratory; response; reverse genetics; severe COVID-19; virus host interaction

Human betacoronaviruses induce a wide spectrum of respiratory disease. MERS-CoV (MERS) and SARS-CoV- 2 (SARS-2), cause severe lethal pneumonia, while SARS-2 can also cause mild to asymptomatic disease in some individuals. In contrast, infections with the “common” respiratory human beta-CoV OC43 are largely limited to the upper respiratory tract. With only a few drugs that show promise against human CoVs, it remains imperative to develop therapeutics for current and future emergent human CoVs. For this, we need to identify and understand the host-virus interactions common to all or different among these viruses. A major focus of our lab has been on the double-stranded (ds)RNA induced host responses to beta-CoVs: interferon production and signaling; oligoadenylate synthetase-ribonuclease L and protein kinase R (PKR), that are both antiviral and pro- inflammatory. We have shown that the conserved CoV replicase encoded nsp15 endoribonuclease (Endo)U reduces dsRNA accumulation and activation of all three pathways while subgenera specific accessory proteins add to the antagonism. Merbeco (MERS-CoV) and embeco (OC43) viruses shut down these pathways effectively; in contrast, the sarbecovirus, SARS-2, replicates in respiratory derived cells despite activation of all three. Preliminary data suggest that downstream effects of RNase L on inflammation and cell death may be more impactful during SARS-2 infection than the modest antiviral effects. PKR and PKR-like ER kinase (PERK), both kinases of the integrated stress response, when activated, phosphorylate protein synthesis initiation factor eIF2a, leading to protein synthesis attenuation, providing an important control point in infection. Activation of PERK also initiates a pathways of the unfolded protein response (UPR) to ER stress, which produces antiviral effects and inflammation. We found that MERS and OC43 infection suppress phosphorylation of eIF2a by preventing PKR activation and through a PERK pathway feedback loop, dephosphorylating eIF2a. In contrast SARS-2 promotes p-eIF2a through both PKR and PERK, but maintains viral protein synthesis. This may occur in part via the CoV replicase nsp1 protein, which promotes selective attenuation of host, but not viral, protein synthesis. Our overall hypothesis is that betacoronaviruses of each subgenus have evolved unique ways to interact with host responses to optimize replication and spread and that these differences influence pathogenic outcomes. We propose to determine: the role of the conserved CoV EndoU and subgenera specific accessory proteins in antagonizing host innate response pathways; the impact of OAS-RNase L activation on viral replication, inflammation and cell death; and the effects of host PKR/PERK and viral nsp1 on control of protein synthesis and virus replication. Our overall goal is to understand the similarities and differences in host interactions among beta-CoVs of three subgenera. Our findings may identify novel therapeutic interventions targeting host or viral proteins and indicate whether they may work as pan-CoV therapies or be unique to each beta-CoV subgenus, and thus help prepare for future CoV outbreaks.

人β冠状病毒可引起广泛的呼吸道疾病。MERS冠状病毒（MERS）和SARS冠状病毒- 2（SARS-2），引起严重的致命性肺炎，而SARS-2也可引起轻度至无症状的疾病， 一些个人。相比之下，“普通”呼吸道人类β-CoV OC 43的感染在很大程度上是有限的。 到上呼吸道只有少数药物显示出对人类冠状病毒的承诺， 必须为当前和未来出现的人类CoV开发治疗方法。为此，我们需要确定 并了解所有这些病毒共同或不同的宿主-病毒相互作用。我们的一个主要重点是 实验室一直在研究双链（ds）RNA诱导宿主对β-CoV的反应：干扰素的产生和 信号传导;寡腺苷酸合成酶-核糖核酸酶L和蛋白激酶R（PKR），这两者都是抗病毒的， 煽动性我们已经证明保守的CoV复制酶编码的nsp 15内切核糖核酸酶（Endo）U 减少dsRNA的积累和激活所有三个途径，而亚属特异性辅助蛋白 增加了对抗性。Merbeco（MERS-CoV）和embeco（OC 43）病毒关闭了这些途径 有效;相反，Sarbecovirus，SARS-2，在呼吸衍生细胞中复制，尽管所有的激活， 三.初步数据表明，RNase L对炎症和细胞死亡的下游作用可能更多。 在SARS-2感染期间，比适度的抗病毒效果更有效。PKR和PKR样ER激酶（PERK），两者 整合应激反应的激酶，当被激活时，磷酸化蛋白质合成起始因子eIF 2a， 导致蛋白质合成减弱，提供感染中的重要控制点。激活PERK也 启动对ER应激的未折叠蛋白反应（UPR）途径，产生抗病毒作用， 炎症我们发现MERS和OC 43感染通过阻止PKR抑制eIF 2a的磷酸化， 激活并通过PERK途径反馈环，使eIF 2a去磷酸化。相反，SARS-2促进了 p-eIF 2a通过PKR和PERK两者，但维持病毒蛋白质合成。这可能部分通过CoV发生 复制酶nsp 1蛋白，其促进宿主蛋白质合成的选择性减毒，但不促进病毒蛋白质合成。我们的整体 一种假说认为，每一个亚属的β冠状病毒都进化出了与宿主相互作用的独特方式 反应，以优化复制和传播，这些差异影响致病的结果。 我们建议确定：保守的CoV EndoU和亚属特异性辅助蛋白在 拮抗宿主先天反应途径; OAS-RNase L活化对病毒复制的影响， 炎症和细胞死亡;以及宿主PKR/PERK和病毒nsp 1对蛋白质合成控制的影响 和病毒复制。我们的总体目标是了解宿主相互作用的相似性和差异， 三个亚属的β-CoV。我们的研究结果可能会确定新的治疗干预靶向主机或病毒 蛋白质，并指出它们是否可以作为泛CoV疗法或对每个β-CoV亚属是独特的， 从而为未来的冠状病毒爆发做好准备。

项目成果

SARS-CoV-2 Delta Variant (AY.3) in the Feces of a Domestic Cat.

• DOI: 10.3390/v14020421
• 发表时间: 2022-02-17
• 期刊: Viruses
• 作者: Lenz OC;Marques AD;Kelly BJ;Rodino KG;Cole SD;Perera RAPM;Weiss SR;Bushman FD;Lennon EM
• 通讯作者: Lennon EM

A Novel Glucocorticoid and Androgen Receptor Modulator Reduces Viral Entry and Innate Immune Inflammatory Responses in the Syrian Hamster Model of SARS-CoV-2 Infection.

• DOI: 10.3389/fimmu.2022.811430
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Rocha SM;Fagre AC;Latham AS;Cummings JE;Aboellail TA;Reigan P;Aldaz DA;McDermott CP;Popichak KA;Kading RC;Schountz T;Theise ND;Slayden RA;Tjalkens RB
• 通讯作者: Tjalkens RB

SARS-CoV-2 infection, neuropathogenesis and transmission among deer mice: Implications for spillback to New World rodents.

• DOI: 10.1371/journal.ppat.1009585
• 发表时间: 2021-05
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Fagre A;Lewis J;Eckley M;Zhan S;Rocha SM;Sexton NR;Burke B;Geiss B;Peersen O;Bass T;Kading R;Rovnak J;Ebel GD;Tjalkens RB;Aboellail T;Schountz T
• 通讯作者: Schountz T

SARS-CoV-2 variants associated with vaccine breakthrough in the Delaware Valley through summer 2021.

2021 年夏季之前，与特拉华谷疫苗突破相关的 SARS-CoV-2 变体。

• DOI: 10.1101/2021.10.18.21264623
• 发表时间: 2021
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Marques,AndrewD;Sherrill-Mix,Scott;Everett,John;Reddy,Shantan;Hokama,Pascha;Roche,AoifeM;Hwang,Young;Glascock,Abigail;Whiteside,SamanthaA;Graham-Wooten,Jevon;Khatib,LaylaA;Fitzgerald,AyannahS;Moustafa,AhmedM;Bianco,Colleen
• 通讯作者: Bianco,Colleen

Partial ORF1ab Gene Target Failure with Omicron BA.2.12.1.

• DOI: 10.1128/jcm.00600-22
• 发表时间: 2022-06-15
• 期刊: Journal of clinical microbiology
• 影响因子: 9.4