Mechanisms of Host Response Modulation by RSV Non-Structural Proteins

RSV 非结构蛋白调节宿主反应的机制

• 批准号: 10667415
• 负责人: Daisy W Leung
• 金额: $ 64.26万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667415
• 关键词: Acute; Adopted; Animal Model; Antibodies; Antiviral Response; Attenuated; Binding; Biochemical; Biochemistry; Cell Culture Techniques; Cell Nucleus; Cells; Child; Childhood; Chromatin; Complex; Development; Disease; Elderly; Enhancers; Epigenetic Process; Exportins; Exposure to; Future; Genes; Genetic; Genetic Transcription; Genomics; Goals; Health; Human; Immune; Immune Evasion; Immune Response Genes; Immune response; Immunity; Immunocompromised Host; Impairment; Individual; Infant; Infection; Integration Host Factors; Interferons; Knowledge; Licensing; Lung; Mediator; Methods; Modeling; Molecular; Monoclonal Antibodies; Mononegavirales; Mutation; Nonstructural Protein; Nuclear; Pathology; Physiological; Play; Pneumovirus; Population; Positioning Attribute; Proteins; Pulmonology; Regulatory Element; Resolution; Respiration; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory syncytial virus; Respiratory syncytial virus RSV proteins; Roentgen Rays; Role; Shapes; Signal Transduction; Structure; Transcriptional Regulation; Viral; Viral Genome; Viral Pathogenesis; Viral Proteins; Virus Diseases; Virus Replication; Work; cell type; effective therapy; epigenetic regulation; epigenome; global health; human pathogen; immunoregulation; insight; interferon antagonist; member; multidisciplinary; multiple myeloma M Protein; mutant; novel; nucleocytoplasmic transport; paralogous gene; prevent; promoter; prophylactic; recombinant virus; response; structural biology; therapeutic target; tool; trafficking; transcription factor; transcriptome; vaccine development

Human respiratory syncytial virus (RSV) is responsible for a major fraction of severe acute respiratory tract infections, including pediatric, elderly, and immunocompromised individuals, and thus has a global impact on human health. Despite this, there are limited prophylactic and specific treatment options available for RSV infections. RSV nonstructural proteins NS1 and NS2, which are unique to RSV among the pneumoviruses, play multiple major roles that are thought to enhance viral infection and to prevent protection from subsequent RSV reinfection. However, many questions remain that are related to how RSV virally encoded proteins shape the host response. Our unpublished preliminary studies show that NS1 partitions to the nucleus in physiologically relevant cell culture models, binds chromatin at promoters and enhancers of immune response genes, and impacts host gene transcription. In addition, we observe that nuclear NS1 interacts with viral proteins NS2 and matrix (M), an indication of further modulation of host factors in the nucleus by RSV viral proteins. Functional correlates of these observations are poorly understood. Based on these novel findings and to fill this knowledge gap, we propose to determine the molecular mechanisms of NS1 as a major modulator of the epigenome and host responses during RSV infection. Nuclear NS1 may also skew antiviral responses while enhancing immune evasion, thereby promoting viral pathogenesis. Our team, with complementary expertise in biochemistry/structural biology, epigenetics, transcriptional regulation, and pulmonology will define the impact of RSV NS1 on host epigenetic transcriptional control, define and characterize the molecular interactions that contribute to nucleocytoplasmic transport of NS1, and determine the impact of RSV NS2 and M protein interactions on NS1 nuclear functions. To obtain mechanistic insights and to assess the impact of these observations during viral infections, we will use an approach that integrates biochemical, structural, genetic, cellular, and virological studies in relevant cell culture models, including primary human lung derived cells. By completing these synergistic Aims, we expect to provide insights into key contributors to disease and define novel targets for antiviral and vaccine development.

人呼吸道合胞病毒（RSV）是导致严重急性呼吸道感染的主要原因，包括儿童、老年人和免疫功能低下的个体，因此对人类健康具有全球影响。尽管如此，RSV感染的预防性和特异性治疗选择有限。RSV非结构蛋白NS 1和NS 2是RSV在肺炎病毒中所特有的，它们发挥着多种主要作用，被认为可以增强病毒感染并防止对随后的RSV再感染的保护。然而，许多问题仍然与RSV病毒编码的蛋白质如何塑造宿主反应有关。我们未发表的初步研究表明，NS 1在生理相关的细胞培养模型中分配到细胞核，在免疫应答基因的启动子和增强子处结合染色质，并影响宿主基因转录。此外，我们观察到核NS 1与病毒蛋白NS 2和基质（M）相互作用，这表明RSV病毒蛋白进一步调节了核中的宿主因子。这些观察结果的功能相关性知之甚少。基于这些新的发现和填补这一知识空白，我们建议确定NS 1作为RSV感染期间表观基因组和宿主反应的主要调节剂的分子机制。核NS 1也可能扭曲抗病毒反应，同时增强免疫逃避，从而促进病毒的发病机制。我们的团队在生物化学/结构生物学，表观遗传学，转录调控和肺病学方面具有互补的专业知识，将确定RSV NS 1对宿主表观遗传转录控制的影响，定义和表征有助于NS 1核质转运的分子相互作用，并确定RSV NS 2和M蛋白相互作用对NS 1核功能的影响。为了获得机制的见解，并评估这些观察结果在病毒感染过程中的影响，我们将使用一种方法，该方法在相关的细胞培养模型中整合了生物化学，结构，遗传，细胞和病毒学研究，包括原代人肺衍生细胞。通过完成这些协同目标，我们希望能够深入了解疾病的关键因素，并确定抗病毒和疫苗开发的新靶点。