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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