Molecular basis for parainfluenza virus infection and host response

副流感病毒感染和宿主反应的分子基础

• 批准号: 8066662
• 负责人: Charles John Russell
• 金额: $ 41.58万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066662
• 关键词: Affect; Antibodies; Antigens; Antiviral Agents; Attenuated; Biological; Biology; Cells; Cessation of life; Characteristics; Child; Childhood; Communicable Diseases; Coronavirus; Cotton Rats; Disease; Filovirus; Future; Generations; Genes; Glycoproteins; Goals; Hospitalization; Human; Immune response; Immunity; Immunocompromised Host; In Vitro; Infection; Mediating; Membrane; Membrane Fusion; Modeling; Modification; Molecular; Mus; Mutation; Parainfluenza Virus Infections; Paramyxovirus; Pathogenesis; Pathogenicity; Pediatric Hospitals; Pharmaceutical Preparations; Property; Proteins; Recombinants; Resolution; Respiratory syncytial virus; Retroviridae; Role; Sendai virus; Serum; Structural Protein; Structure; Surface; Testing; United States; Vaccines; Variant; Viral Fusion Proteins; Virion; Virulence; Virus; Virus Diseases; Virus Replication; Work; base; immunogenicity; immunopathology; influenzavirus; neutralizing antibody; novel strategies; novel therapeutics; parainfluenza virus; pathogen; protein structure; public health relevance; respiratory; therapeutic target; vaccine candidate; vaccine development; vector; vector vaccine; vector-based vaccine; virus pathogenesis

DESCRIPTION (provided by applicant): Human parainfluenza viruses (HPIV1, 2, and 3) are the second leading cause of pediatric hospitalization in the United States due to respiratory viral infection. In the immunocompromised, these pathogens also cause prolonged illness and often death. Our long-term goal is to understand how parainfluenza viruses cause disease and induce immunity so that specific antiviral drugs and vaccines, which are currently unavailable, can be developed. The parainfluenza virus fusion (F) envelope glycoprotein is found on the surfaces of virions and infected cells. We hypothesize that the parainfluenza virus F protein regulates viral infection and the host response by its multiple functional activities of promoting membrane fusion and immunogenicity. Recent determinations of high-resolution structures of parainfluenza virus F proteins in both prefusion (native) and postfusion (hairpin) forms now provides a structural basis to investigate molecular mechanisms by which the F protein regulates the biology of parainfluenza viruses. The objective of this application is to understand how structural changes by parainfluenza virus F proteins are regulated (Specific Aim 1) and how they help determine pathogenicity (Specific Aim 2) and immunogenicity (Specific Aim 3). In Specific Aim 1, we will determine how HPIV3 F protein structural changes are regulated during membrane fusion. We will test the hypothesis that F protein refolding and membrane fusion are regulated by residues in regions that undergo dramatic structural changes between prefusion and postfusion F protein structures. Mutational analyses on heptad repeat (HR) regions in the HPIV3 F protein will be performed. Understanding how the F protein structure is stabilized and then triggered to refold during membrane fusion will provide a greater understanding of protein-mediated membrane fusion, a fundamental mechanism common to all enveloped viruses. In Specific Aim 2, we will investigate how F protein fusogenicity causes Sendai virus pathogenicity in mice. We will determine mechanisms by which a hyperfusogenic recombinant Sendai virus variant rSeV-F-L179V and other virus variants induce greater pathogenicity in mice. Studying Sendai virus pathogenesis in its natural host, the mouse, will provide an understanding of the role of the F protein in pathogenesis. These studies will also support efforts to treat human parainfluenza virus infection with novel therapeutics. In Specific Aim 3, we will increase the immunogenicity of a Sendai virus vaccine that expresses the HPIV3 F protein. We will determine how modifications of the Sendai virus vector and the expressed structural form of the HPIV3 F protein antigen help determine immunogenicity and potential immunopathology. Because the F protein is conserved among all of the paramyxoviruses, an understanding of how the HPIV3 F protein determines immunity and immunopathology may assist in the development of vaccines for other important respiratory paramyxoviruses like the other human parainfluenza viruses (HPIV1, HPIV2, and HPIV4) and respiratory syncytial virus (RSV). PUBLIC HEALTH RELEVANCE: Human parainfluenza viruses are a leading cause of hospitalization of U.S. children, and they can be deadly in immunocompromised patients. Our proposed work will help understand how parainfluenza viruses cause disease at the molecular level. These studies will help efforts to develop new drugs and vaccines against parainfluenza viruses.

描述(申请人提供)：人类副流感病毒(HPIV1、2和3型)是美国儿科住院治疗的第二大原因，原因是呼吸道病毒感染。在免疫功能受损的人中，这些病原体还会导致旷日持久的疾病，甚至经常死亡。我们的长期目标是了解副流感病毒如何致病和诱导免疫，以便开发目前无法获得的特定抗病毒药物和疫苗。副流感病毒融合(F)包膜糖蛋白存在于病毒粒子和感染细胞的表面。我们推测副流感病毒F蛋白通过其促进膜融合和免疫原性等多种功能调节病毒感染和宿主反应。最近对副流感病毒F蛋白在融合前(天然)和融合后(发夹)形式的高分辨结构的测定，为研究F蛋白调节副流感病毒生物学的分子机制提供了结构基础。这项应用的目的是了解副流感病毒F蛋白的结构变化是如何调节的(特异性目标1)，以及它们如何帮助确定致病性(特异性目标2)和免疫原性(特异性目标3)。在特定的目标1中，我们将确定HPIV3F蛋白在膜融合过程中的结构变化是如何调节的。我们将检验这一假设，即F蛋白的折叠和膜融合是由融合前和融合后F蛋白结构发生戏剧性结构变化的区域的残基调控的。将对HPIV3F蛋白中的七肽重复(HR)区域进行突变分析。了解F蛋白结构是如何在膜融合过程中稳定并随后被触发折叠的，将有助于更好地理解蛋白质介导的膜融合，这是所有被膜病毒共有的基本机制。在特定的目标2中，我们将研究F蛋白的融合如何导致仙台病毒在小鼠中致病。我们将确定超强致病性重组仙台病毒变异株rSeV-F-L179V和其他病毒变异株在小鼠中诱导更强致病性的机制。研究仙台病毒在其自然宿主--小鼠体内的致病机制，将有助于理解F蛋白在致病机制中的作用。这些研究还将支持用新的疗法治疗人类副流感病毒感染的努力。在具体目标3中，我们将提高表达HPIV3F蛋白的仙台病毒疫苗的免疫原性。我们将确定仙台病毒载体的修饰和HPIV3F蛋白抗原的表达结构形式如何有助于确定免疫原性和潜在的免疫病理学。由于F蛋白在所有副粘病毒中是保守的，了解HPIV3 F蛋白如何决定免疫和免疫病理学可能有助于开发其他重要的呼吸道副粘病毒疫苗，如其他人类副流感病毒(HPIV1、HPIV2和HPIV4)和呼吸道合胞病毒(RSV)。 公共卫生相关性：人类副流感病毒是导致美国儿童住院的主要原因，对免疫功能低下的患者来说，它们可能是致命的。我们提出的工作将有助于在分子水平上了解副流感病毒如何导致疾病。这些研究将有助于开发针对副流感病毒的新药和疫苗。