A host-dependent mechanism controlling influenza virus infection by suppressing viral RNA synthesis

通过抑制病毒RNA合成来控制流感病毒感染的宿主依赖性机制

• 批准号: 10555188
• 负责人: Ivan Marazzi
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10555188
• 关键词: Address; Affect; Agreement; Binding; Biochemical; Biological; Catabolism; Cell Nucleus; Cells; Complementary RNA; Complex; Cytoplasm; Cytoplasmic Receptors; DNA-Directed RNA Polymerase; Data; Dedications; Disease; Double-Stranded RNA; Enzymes; Epidemic; Exonuclease; Family; Future; Gene Expression; Genetic; Genetic Transcription; Genome; Host Defense Mechanism; Human; Immune response; Immunoprecipitation; In Vitro; Infection; Influenza A virus; Innate Immune System; Integration Host Factors; Kinetics; Knockout Mice; Knowledge; Label; Laboratories; Light; Metabolic; Methods; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Nuclear; Nuclear Proteins; Nucleoproteins; Orthomyxoviridae; Pattern; Pattern recognition receptor; Physiological; Polymerase; Predisposition; Process; Protein Family; Proteins; Public Health; RNA; RNA Binding; RNA Degradation; RNA Viruses; RNA chemical synthesis; Regulation; Research; Research Project Grants; Ribonucleoproteins; Role; Seasons; Signal Transduction; Societies; Specificity; Techniques; Testing; Viral; Viral Genes; Viral Genome; Viral Pathogenesis; Virion; Virus; Virus Assembly; Virus Diseases; Virus Replication; antagonist; biotypes; disorder control; experimental study; genome-wide; genomic RNA; improved; in vivo; influenza infection; influenza virulence; influenzavirus; insight; loss of function; molecular recognition; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; pandemic disease; pathogen; receptor; respiratory pathogen; sensor; tripolyphosphate; viral RNA; viral genomics

Influenza A virus (IAV) is a major human respiratory pathogen that causes seasonal epidemics and occasional pandemics. The virus is a segmented, negative stranded RNA virus that, unlike most other RNA viruses, replicates its genome in the nucleus of infected cells. Genome replication yields a complementary RNA (cRNA) and a viral genomic RNA (vRNA). Both cRNA and vRNA contain a 5' triphosphate (ppp) which is recognized by the innate immune system by pattern recognition receptors (PRRs). Cytosolic sensors have been implicated in the specific recognition of influenza virus. Whether IAV can also be recognized in the nucleus is unknown. To address this, we screened nuclear proteins that, based on enzymatic features, may recognize viral RNA. Our preliminary results indicate that the protein DXO, a nuclear enzyme with 5'->3' pyrophosphohydrolase activity, can both recognize and degrade IAV RNA in vitro and in infected cells. We will study the mechanism and impact of DXO activity using biochemical and gene expression studies (Aims 1-2). We will examine DXO activity in vivo using a knock-out mouse model that we recently generated (Aim 3). These studies will provide novel mechanistic insights into how viral RNA expression is controlled along with elucidating the role of viral RNA catabolism in IAV pathogenesis, thus instructing new therapeutic avenues for disease eradication.

甲型流感病毒（IAV）是一种主要的人类呼吸道病原体，可引起季节性流行和偶尔的大流行。该病毒是一种分节的负链RNA病毒，与大多数其他RNA病毒不同，它在受感染细胞的细胞核中复制其基因组。基因组复制产生互补RNA （cRNA）和病毒基因组RNA （vRNA）。cRNA和vRNA都含有一个5'三磷酸（ppp），由先天免疫系统通过模式识别受体（PRRs）识别。细胞质传感器与流感病毒的特异性识别有关。IAV是否也能在细胞核中被识别尚不清楚。为了解决这个问题，我们根据酶的特性筛选了可能识别病毒RNA的核蛋白。我们的初步结果表明，DXO蛋白是一种具有5‘->3’焦磷酸水解酶活性的核酶，在体外和感染细胞中都能识别和降解IAV RNA。我们将通过生化和基因表达研究来研究DXO活性的机制和影响（目的1-2）。我们将使用我们最近生成的敲除小鼠模型来检测DXO在体内的活性（Aim 3）。这些研究将为病毒RNA表达如何被控制提供新的机制见解，并阐明病毒RNA分解代谢在IAV发病机制中的作用，从而指导疾病根除的新治疗途径。

项目成果

Author Correction: Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4.

作者更正：克隆扩增的 CD8 T 细胞是肌萎缩侧索硬化症的特征-4。

• DOI: 10.1038/s41586-022-05184-0
• 发表时间: 2022
• 期刊: Nature
• 影响因子: 64.8
• 作者: Campisi,Laura;Chizari,Shahab;Ho,JessicaSY;Gromova,Anastasia;Arnold,FrederickJ;Mosca,Lorena;Mei,Xueyan;Fstkchyan,Yesai;Torre,Denis;Beharry,Cindy;Garcia-Forn,Marta;Jiménez-Alcázar,Miguel;Korobeynikov,VladislavA;Prazich,Jack;F
• 通讯作者: F

DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells.

DNMT3A单倍不足会导致成熟人类免疫细胞增强子的二分法DNA甲基化缺陷。

• DOI: 10.1084/jem.20202733
• 发表时间: 2021-07-05
• 期刊: The Journal of experimental medicine
• 作者: Lim JY;Duttke SH;Baker TS;Lee J;Gambino KJ;Venturini NJ;Ho JSY;Zheng S;Fstkchyan YS;Pillai V;Fajgenbaum DC;Marazzi I;Benner C;Byun M
• 通讯作者: Byun M

Generation of host-directed and virus-specific antivirals using targeted protein degradation promoted by small molecules and viral RNA mimics.

• DOI: 10.1016/j.chom.2023.05.030
• 发表时间: 2023-06
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Nan Zhao;J. Ho;Fanye Meng;Simin Zheng;A. Kurland;Lu Tian;Martha G Rea-Moreno;Xiangyang Song;Ji-Seon Seo;H. Kaniskan;A. J. T. te Velthuis;D. Tortorella;Ya-Wen Chen;Jeffrey R. Johnson;Jian Jin;Ivan Marazzi

A small nucleosome from a weird virus with a fat genome.

来自具有脂肪基因组的奇怪病毒的小核小体。

• DOI: 10.1016/j.molcel.2021.08.014
• 发表时间: 2021
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Vannini,Alessandro;Marazzi,Ivan
• 通讯作者: Marazzi,Ivan