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Host determinants of enterovirus RNA replication and in vivo neuropathogenesis

肠道病毒RNA复制和体内神经发病机制的宿主决定因素

基本信息

批准号：
10209690
负责人：
Jan E Carette
金额：
$ 54.72万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10209690
关键词：
Actins Acute Address Biology Cell physiology Cells Child Common Cold Communicable Diseases Complex Coxsackie Viruses Cryoelectron Microscopy Crystallography Data Enteral Enterovirus Enterovirus 68 Enterovirus Infections Family Picornaviridae Genes Genome Goals Growth Health Human Human poliovirus Immunity Immunocompetent In Vitro Infection Injections Integration Host Factors Invaded Knock-out Knowledge Medical Methods Methylation Methyltransferase Modeling Molecular Mus Mutation Myocarditis Neurologic Symptoms Neuropathogenesis Oral Paralysed Pathogenesis Play Poliomyelitis Polyproteins Protein Methylation Protein Methyltransferases Proteins Proteomics RNA Viruses RNA replication Regulation Rhinovirus Rhinovirus infection Role Site Structure Testing Therapeutic Intervention Tissues Translations Veterinary Medicine Viral Viral Nonstructural Proteins Viral Pathogenesis Viremia Virus Virus Diseases Virus Replication acute flaccid myelitis asthma exacerbation cell type human disease in vivo innate immune mechanisms insight member microbial mouse model neonate new therapeutic target novel novel strategies oral infection pathogen relating to nervous system screening transmission process viral RNA virus host interaction

项目摘要

PROJECT SUMMARY Pathogens have evolved to co-opt cellular functions to support their replication and spread while inactivating innate immune mechanisms that restrict their growth. Discovery and characterization of cellular components that regulate pathogenesis hold promise for revealing new approaches to treat infectious diseases. Enteroviruses (EVs) comprise a large genus of single-stranded RNA viruses of positive polarity whose members cause a number of important human diseases such as poliomyelitis, myocarditis, acute flaccid paralysis and the common cold. How EVs co-opt cellular functions to promote replication and cause pathogenesis is incompletely understood. Through robust, unbiased knockout screening approaches, we have discovered that the protein methyltransferase SETD3 is required for infection by a broad range of human EVs. We showed that enterovirus replication is severely hampered in human cells lacking SETD3 and that the block occurs during the RNA replication step. SETD3 is a methyltransferase that mono-methylates actin, thereby regulating actin function. However, we found that methyltransferase activity of SETD3 is not required for its role in viral replication indicating that enteroviruses’ reliance on SETD3 is independent of actin methylation. We further showed that SETD3 interacts with the viral nonstructural 2A protein of several enteroviruses. SETD3 is critically important for in vivo pathogenesis as we show that Setd3-/- mice are completely protected from lethal intracranial inoculation with EV-A71 in a neonate model. These findings demonstrate that SETD3 controls pathogenesis for a large class of viruses with a strong impact on human health including non-polio EVs that can cause severe neurological symptoms (EV-A71, EV-D68). In this application, we will determine the specific role of SETD3 in viral RNA replication, structurally characterize the interaction between SETD3 and 2A, and test the hypothesis that SETD3’s interactions with viral nonstructural proteins are a novel molecular mechanism by which EVs hijack cellular machinery to enable genome amplification. Furthermore, to study the in vivo role of SETD3 in a mouse model that recapitulates more faithfully the transmission cycle and pathogenesis of enteric enteroviruses, we will develop and apply an oral infection model of EV-A71 in immune-competent mice. Our results will provide details on the molecular mechanisms by which host factors promote enteroviral RNA replication, reveal how non- catalytic functions of methyltransferases act in microbial pathogenesis and uncover the in vivo role of SETD3 in promoting EV-A71 replication in diverse cell types involved in initial replication, systemic spread and ultimately in neuropathogenesis.

项目总结