Defective Viral genomes in RSV pathogenesis

RSV 发病机制中有缺陷的病毒基因组

• 批准号: 9922869
• 负责人: Carolina B. Lopez
• 金额: $ 12.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-03 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922869
• 关键词: Admission activity; Age; Antiviral Agents; Antiviral Response; Antiviral Therapy; Automobile Driving; Back; Biological Markers; Biology; Bronchiolitis; Cells; Cessation of life; Child; Childhood; Clinical; Critical Care; Custom; Data; Defective Viruses; Detection; Disease; Elderly; Family; Frequencies; Gene Expression; Gene Expression Profile; Generations; Genetic; Genome; Goals; Health; Hospitalization; Human; Immune; Immune response; Immunocompromised Host; Impairment; In Vitro; Inclusion Bodies; Infant; Infection; Investigation; Kinetics; Laboratories; Length; Life; Lower Respiratory Tract Infection; Mechanical ventilation; Mediating; Molecular; Molecular Biology; Mus; Mutation; Outcome; Pathogenesis; Pathology; Patients; Population; Production; RNA; Research; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Role; Sampling; Severity of illness; Signal Transduction; Site; Technology; Testing; Therapeutic; Therapeutic Uses; Vaccine Therapy; Viral; Viral Genome; Viral Load result; Viral Pathogenesis; Viral Respiratory Tract Infection; Virus; Virus Diseases; Virus Replication; antiviral immunity; asthma exacerbation; base; bioinformatics tool; cohort; experimental study; follow-up; healthy volunteer; high risk; immunosuppressed; improved; in vivo; influenzavirus; microscopic imaging; mortality; outcome forecast; parainfluenza virus; pathogen; primary outcome; recombinant virus; respiratory; response; secondary outcome; stress granule; therapy development; tool; virus host interaction; whole genome

Summary Our laboratory recently revealed a critical role for defective viral genomes (DVGs), which are generated during most viral infections, as primary inducers of antiviral immunity in response to many respiratory viral infections. Importantly, detection of DVGs in respiratory secretions from children infected with respiratory syncytial virus (RSV) correlates with evidence of strong antiviral responses, supporting accumulating evidence of a critical role for DVGs in regulating the pathogenesis of RSV. However, study of the biology and clinical impact of DVGs has been slow due, in part, to lack of appropriate technology, and details of the mechanisms that regulate DVG generation and interaction with the host remain unknown. Here we propose to take advantage of important technical advances, including our ability to distinguish DVGs from full-length viral genomes at a single cell level, to significantly improve our understanding of DVG generation and activity during infection with RSV. This pathogen is the major cause of hospitalizations of infants and can cause severe illness and even death in the elderly and the immunosuppressed. Our overarching hypothesis is that DVGs are primary modulators of viral pathogenesis in humans and that their immunostimulatory activity can be harnessed to minimize viral-associated disease. In this proposal, we will follow up on preliminary data challenging the current paradigm that DVG generation initiates randomly during virus replication, and will define viral signatures that regulate the generation of RSV DVGs, thereby advancing strategies to manipulate the DVG content during infection for research and potential therapeutic gain (Aim 1). In addition, we will take advantage of our ability to distinguish DVGs from full-length viral genomes within a cell to understand unique DVG-host interactions that regulate the induction of antiviral immunity during RSV infection (Aim 2). Lastly, we will use unique cohorts of clinical samples readily available to us, to assess the impact of DVGs on the clinical outcome of RSV infection and establish the relationship between DVG levels, disease severity, and host response in humans (Aim 3).

总结 我们的实验室最近揭示了有缺陷的病毒基因组（DVG）的关键作用，这些基因组是在 大多数病毒感染，作为主要诱导剂的抗病毒免疫反应，许多呼吸道病毒感染。 重要的是，检测呼吸道合胞病毒感染儿童呼吸道分泌物中的DVG (RSV)与强抗病毒反应的证据相关，支持一个关键的 DVG在调节RSV发病机制中的作用。然而，研究的生物学和临床影响， DVG进展缓慢，部分原因是缺乏适当的技术和机制细节， 调节DVG的产生和与宿主的相互作用仍然未知。在这里，我们建议利用 重要的技术进步，包括我们区分DVG和全长病毒基因组的能力， 单细胞水平，以显着提高我们的理解DVG的产生和活动期间感染 RSV。这种病原体是婴儿住院的主要原因，可导致严重疾病， 老年人和免疫抑制者的死亡率。我们的首要假设是DVG是主要的 在人类中的病毒发病机制的调节剂，并且它们的免疫刺激活性可以被利用， 最大限度地减少病毒相关疾病。在这份提案中，我们将跟进对 目前的范式是，DVG生成在病毒复制期间随机启动，并将定义病毒 调节RSV DVG生成的特征，从而推进操纵DVG的策略 感染期间的含量，用于研究和潜在的治疗增益（目的1）。此外，我们将利用 我们有能力区分DVG与细胞内的全长病毒基因组，以了解独特的DVG宿主 在RSV感染期间调节抗病毒免疫诱导的相互作用（目的2）。最后，我们将使用 我们可以随时获得独特的临床样本队列，以评估DVG对临床结局的影响 RSV感染，并建立DVG水平，疾病严重程度和宿主反应之间的关系， 人类（目标3）。