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: 7918604
• 负责人: Charles John Russell
• 金额: $ 42万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918604
• 关键词: Affect; Antibodies; Antigens; Antiviral Agents; Attenuated; Biological; Biology; Cells; Cessation of life; Characteristics; Child; Childhood; Coronavirus; Cotton Rats; Disease; Drug Formulations; F-Glycoprotein SV; Filovirus; Future; Glycoproteins; Goals; Hospitalization; Human; Immune response; Immunity; Immunocompromised Host; In Vitro; Infection; Life; Mediating; Membrane; Membrane Fusion; Modeling; 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; Structure; Surface; Testing; United States; Vaccines; Variant; Viral Fusion Proteins; Virion; Virus; Virus Diseases; Work; abstracting; base; immunogenicity; immunopathology; influenzavirus; neutralizing antibody; novel therapeutics; parainfluenza virus; pathogen; protein structure; recombinant virus; respiratory; therapeutic target; vaccine candidate; vaccine development; vector; vector vaccine; virus pathogenesis

ABSTRACT: 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 structural changes by PIV F proteins 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 F proteins of HPIV3 and Sendai virus will be performed. Understanding how F protein structures are 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 determine how the structural form of HPIV3 F protein determines immunogenicity using recombinant Sendai virus (rSeV) vaccine vectors that express different structural forms of the HPIV3 F envelope glycoprotein. Because the F protein is conserved among all of the paramyxoviruses, an understanding of how the structural form of 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).

摘要： 人类副流感病毒（HPIV 1、2和3）是美国儿科住院的第二大原因。 美国因呼吸道病毒感染。在免疫功能低下的人中，这些病原体也会引起 长期患病，经常死亡。我们的长期目标是了解副流感病毒是如何引起 疾病和诱导免疫力，使目前无法获得的特定抗病毒药物和疫苗， 发展。副流感病毒融合（F）包膜糖蛋白存在于病毒粒子的表面， 被感染的细胞我们假设副流感病毒F蛋白调节病毒感染和宿主 通过其促进膜融合和免疫原性的多种功能活性来应答。最近 融合前（天然）和融合后（非天然）中副流感病毒F蛋白的高分辨率结构测定 融合后（发夹）形式现在提供了一个结构基础，研究分子机制，通过该机制，F 蛋白质调节副流感病毒的生物学。本应用程序的目的是了解如何 副流感病毒F蛋白的结构变化受到调节（具体目标1）以及它们如何起作用 确定致病性（特异性目标2）和免疫原性（特异性目标3）。具体目标1： 确定PIV F蛋白的结构变化在膜融合过程中是如何调节的。我们将测试 假设F蛋白的重折叠和膜融合是由经历了 融合前和融合后F蛋白结构之间的显著结构变化。突变分析 将对HPIV 3和仙台病毒的F蛋白中的七肽重复（HR）区域进行分析。了解如何 F蛋白结构稳定，然后在膜融合过程中触发重新折叠，将提供更大的 了解蛋白质介导的膜融合，一个共同的基本机制，所有包膜 病毒在具体目标2中，我们将研究F蛋白融合性如何导致仙台病毒在大肠杆菌中的致病性。 小鼠我们将确定一种超致性重组仙台病毒变体rSeV-F- L179 V和其他病毒变体在小鼠中诱导更大的致病性。仙台病毒致病机制的研究 自然宿主，小鼠，将提供F蛋白在发病机制中的作用的理解。这些 研究还将支持用新的治疗剂治疗人类副流感病毒感染的努力。在特定 目的3，我们将确定HPIV 3 F蛋白的结构形式如何决定免疫原性， 表达HPIV 3 F不同结构形式的重组仙台病毒（rSeV）疫苗载体 包膜糖蛋白由于F蛋白在所有副粘病毒中是保守的， 了解HPIV 3 F蛋白的结构形式如何决定免疫力和免疫病理学 可能有助于其他重要的呼吸道副粘病毒疫苗的开发， 人副流感病毒（HPIV 1、HPIV 2和HPIV 4）和呼吸道合胞病毒（RSV）。