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Zika Virus Capsid Protein Mediated Blockage of host microRNA machinery

寨卡病毒衣壳蛋白介导的宿主 microRNA 机制的阻断

基本信息

批准号：
10594437
负责人：
Zhen Zhao
金额：
$ 43.4万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594437
关键词：
African Animals Binding Bioinformatics Biological Assay Brain Brazil Capsid Capsid Proteins Cell physiology Cells Code Communicable Diseases Congenital Abnormality Country Development Dicer Enzyme Disease Disease Outbreaks Embryo Endoribonucleases Eukaryotic Cell Family Fetal Growth Retardation Flaviviridae Flavivirus Gene Expression Regulation Genes Genome Human Immune Evasion Impairment In Vitro Infection Innate Immune System International Invertebrates Investigation Life Cycle Stages Link Maps Mediating Messenger RNA MicroRNAs Microcephaly Modeling Molecular Molecular Target Mus Natural Immunity Nervous System Neurologic Nucleotides Outcome Pathogenesis Pathway interactions Placenta Plants Play Pregnancy Process Production Proteins RNA RNA Interference RNA Viruses RNA-Induced Silencing Complex Regulation Reporting Resistance Ribonuclease III Ribonucleases Role Small Interfering RNA Small RNA Surveillance Program System Testing Therapeutic Variant Viral Viral Genome Viral Proteins Virulence Virus Virus Replication ZIKA ZIKV infection Zika Virus congenital zika syndrome drug development fetal fighting fungus human disease in utero in vivo induced pluripotent stem cell insight member mouse model nerve stem cell nervous system disorder neural neurodevelopment neurogenesis novel strategies pregnant prenatal programs protein protein interaction response stem stem cells therapeutic development transcriptome sequencing

项目摘要

SUMMARY Zika virus (ZIKV) is a single-stranded RNA virus of the Flaviviridae family. It rapidly spread worldwide during 2015-2016 and is causally associated with fetal microcephaly, intrauterine growth retardation, and other congenital malformations. ZIKV is reported to infect placenta and fetal brain during pregnancy, particularly targeting human neural stem and progenitor cells (NSCs). Among the flavivirus family, only ZIKV is linked to microcephaly, suggesting uniqueness of ZIKV infection compared to other members, which calls for a better understanding of the molecular drivers of ZIKV immune evasion and pathogenesis in fetal brain. In addition, host molecular targets of ZIKV proteins remain elusive, which not only limits our understanding of ZIKV infection and pathogenesis, but also impedes anti-ZIKV drug development. Since the ZIKV outbreak in 2015, we have focused on understanding the complexity of ZIKV infection and pathogenesis of microcephaly. To fully understand the roles of viral proteins during ZIKV life cycle, we established the ZIKV-host interactome in human iPSC-derived NSCs. By analyzing this ZIKV-host interactome, we found that the key microRNA processing protein DICER was the top target of ZIKV capsid protein, and DICER deficiency facilitated ZIKV infection in mouse embryonic NSCs. Dysregulation of microRNAs has been associated with many human disease diseases, including developmental neurological disorders such as microcephaly. More importantly, DICER-dependent microRNA production is commonly used by plants, fungi and invertebrates, and remains active in mammalian stem cells to produce antiviral small RNAs from the viral genomes, which inhibits viral replication via RISC-mediated RNA interference. Mechanistically, we further identified that ZIKV capsid directly interacts with DICER and blocks its ribonuclease activity, dampening the production of both viral interfering RNAs and host microRNAs that are essential for neurogenesis. Therefore, we hypothesize that ZIKV can efficiently suppress the DICER-mediated antiviral viRNA pathway in host cells with its capsid protein; and by antagonizing host microRNA machinery, ZIKV capsid also intervenes neural development and causes microcephaly and other birth defects. Under the current application, we propose to further investigate capsid-dependent suppression of DICER function as a unique determinant of ZIKV immune evasion and pathogenesis, using different ZIKV strains and capsid variants in both human fetal NSCs and a mouse model of prenatal infection. By understanding the unique role of DICER in ZIKV infection and its associated microcephaly, we hope to define a capsid-dependent difference between the Brazilian and African strains (AIMs 1-2), and provide a proof-of-concept whether boosting this viRNA-dependent innate immune system is applicable as a novel approach to reverse the pathogenesis of ZIKV in fetal brain (AIMs 2-3). The outcomes of this application will also provide broader insight for other CNS infectious diseases.

总结