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Role of ADAM9 in viral RNA sensing and antiviral innate immunity

ADAM9 在病毒 RNA 传感和抗病毒先天免疫中的作用

基本信息

批准号：
10753041
负责人：
Michaela Ulrike Gack
金额：
$ 26.52万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-02 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753041
关键词：
2019-nCoV Adaptor Signaling Protein Adult Affect Animal Model Antiviral Response Binding Biochemical Biological Biological Models Brain Cardiac Cell Nucleus Cell surface Cells Characteristics Chemosensitization Complex Coronavirus Coronavirus Infections Coxsackie Viruses Cytoplasmic Tail Cytosol Data Disintegrins Encephalitis Encephalomyocarditis virus Family Family Picornaviridae Filament Genes Genetic Transcription Grant Heart Human IRF3 gene Immune Immune system Immunologic Receptors Impairment Infection Inflammation Inflammatory Influenza A virus Innate Immune Response Integration Host Factors Interferon Activation Interferon Type I Interferon-beta Interferons Knock-out Knockout Mice Knowledge Lead Lentivirus Vector Link Mass Spectrum Analysis Measures Mediating Metalloproteases Mitochondria Mitochondrial Proteins Molecular Morbidity - disease rate Mus Myocarditis Natural Immunity Nucleic Acids Pathogenesis Pathway interactions Picornaviridae Infections Post-Translational Protein Processing Process Production Protein Dephosphorylation Protein Family Proteins RNA RNA Binding RNA Virus Infections RNA Viruses Regulation Research Personnel Role SH3 Domains STAT1 gene Sendai virus Series Signal Pathway Signal Transduction Surface TBK1 gene Tissues Tretinoin Ubiquitination Vesicular stomatitis Indiana virus Viral Viral Encephalitis Viral Genome Viral Pathogenesis Virus Virus Diseases Virus Replication Western Blotting Wild Type Mouse cell type cytosolic receptor detection platform experimental study helicase in vivo innate immune sensing knock-down melanoma member mortality mutant novel prevent protein activation protein protein interaction receptor reconstitution recruit response sensor single-cell RNA sequencing transcriptome sequencing viral RNA viral myocarditis

项目摘要

Project Abstract Picornavirus infections are a leading cause of viral encephalitis and myocarditis in humans. These viral infections can cause substantial inflammatory changes in the brain and heart and lead to significant morbidity and mortality. The immune system detects picornavirus infections, and other single-stranded RNA (ssRNA) viruses, via DEAD/H-box (DDX) helicases that sense cytosolic viral ssRNA and initiate the protective interferon (IFN) response. Two DDX helicases critical in this process are retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Both RIG-I and MDA5 are members of the RIG-I-like receptor (RLR) family of RNA-sensing helicases. RIG-I is known to sense negative-sense ssRNA (–ssRNA) viruses (e.g., Sendai virus or vesicular stomatitis virus), while MDA5 is the major sensor for RNA from picornaviruses and other positive-sense ssRNA (+ssRNA) viruses including SARS-CoV2 and other coronaviruses. How MDA5 is activated and regulated is currently not well known, which is in striking contrast to RIG-I for which the activating mechanisms have been elucidated in detail. To study the pathogenesis of myocarditis and encephalitis, researchers have used a prototypical member of the picornavirus family, encephalomyocarditis virus (EMCV). Using EMCV, we demonstrated an important role for the A disintegrin and metalloproteinase protein (ADAM9) in viral pathogenesis. We discovered that mice lacking ADAM9 rapidly succumb to EMCV infection without mounting the characteristic IFN response seen in wild-type mice. Our data indicate a novel role for ADAM9 in viral RNA-induced IFN production through the DDX helicase MDA5. In EMCV infection, MDA5 is the sensor that recognizes viral RNA and initiates a signaling cascade that leads to activation of the mitochondrial antiviral signaling (MAVS) pathway and subsequent IFN production. IFN production is triggered when the viral genome interacts with nucleic acid sensors in the host cell to activate downstream pathways. The host IFN response is crucial to protect the host by limiting virus replication. We hypothesize that ADAM9’s role in viral-induced IFN production is mediated through the MDA5-MAVS pathway. The role of ADAM9 in regulating the IFN response to diverse RNA viruses, including picornaviruses and coronaviruses, will be defined in terms of its effects on the ability of MDA5 to interact with viral RNA and its effect on protein-protein interactions and post-translational modifications of MAVS pathway adapters and effector proteins. Through these experiments, we will define new pathways of IFN activation and better define the pathogenesis of RNA viruses in an animal model system for studying encephalitis and myocarditis.

项目摘要小核糖核酸病毒感染是人类病毒性脑炎和心肌炎的主要原因。这些病毒感染可引起大脑和心脏的实质性炎症变化， and mortality.免疫系统检测小核糖核酸病毒感染和其他单链RNA（ssRNA）病毒，通过DEAD/H-box（DDX）解旋酶，其感测胞质病毒ssRNA并启动保护性干扰素 (IFN)反应在该过程中关键的两种DDX解旋酶是视黄酸诱导基因I（RIG-I）和黑色素瘤分化相关基因5（MDA 5）。RIG-I和MDA 5都是RIG-I-like的成员。 RNA传感解旋酶的受体（RLR）家族。已知RIG-I感测负义ssRNA（-ssRNA）病毒（例如，仙台病毒或水泡性口炎病毒），而MDA 5是仙台病毒RNA的主要传感器小核糖核酸病毒和其他正义ssRNA（+ssRNA）病毒，包括SARS-CoV 2和其他冠状病毒MDA 5是如何被激活和调节的，目前还不清楚，这与MDA 5是如何被激活和调节的形成鲜明对比。 RIG-I，其激活机制已被详细阐明。为了研究心肌炎和脑炎的发病机制，研究人员使用了一种典型的小核糖核酸病毒家族成员，脑心肌炎病毒（EMCV）。使用EMCV，我们演示了解整合素和金属蛋白酶A蛋白（ADAM 9）在病毒发病机制中的重要作用。我们发现缺乏ADAM 9的小鼠迅速死于EMCV感染，而没有增加在野生型小鼠中观察到IFN应答。我们的数据表明ADAM 9在病毒RNA诱导的IFN-γ中的新作用通过DDX解旋酶MDA 5生产。在EMCV感染中，MDA 5是识别病毒RNA并启动信号级联的传感器，导致线粒体抗病毒信号传导（MAVS）途径的激活和随后的IFN产生。当病毒基因组与宿主细胞中的核酸传感器相互作用以激活下游路径。宿主IFN应答对于通过限制病毒复制来保护宿主是至关重要的。我们假设ADAM 9在病毒诱导的IFN产生中的作用是通过MDA 5-MAVS途径介导的。 ADAM 9在调节IFN对不同RNA病毒应答中的作用，包括小RNA病毒和冠状病毒，将根据其对MDA 5与病毒RNA相互作用能力的影响及其对MAVS途径衔接子的蛋白质-蛋白质相互作用和翻译后修饰的影响，效应蛋白通过这些实验，我们将确定IFN激活的新途径，并更好地确定 RNA病毒在研究脑炎和心肌炎的动物模型系统中的发病机制。