Prevention of adenovirus pathogenesis through downregulation of the apical adenovirus receptor

通过下调顶端腺病毒受体预防腺病毒发病机制

基本信息

批准号：
9445681
负责人：
Katherine Julie Excoffon
金额：
$ 37.5万
依托单位：
WRIGHT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9445681
关键词：
Acute Adenovirus Infections Adenoviruses Adult Respiratory Distress Syndrome Alpha Cell Animals Apical BAIAP1 gene Binding Biological Assay Biological Models Cell Adhesion Molecules Cell Nucleus Cells Cleaved cell Cotton Rats Coxsackie B Viruses Coxsackie Viruses Cyclophosphamide Data Degradation Pathway Development Discipline Down-Regulation Epithelial Cells Epithelium Exons Future Goals Histologic Human Immunocompetent In Vitro Individual Infection Infection prevention Interruption Intervention Kinetics Knowledge Lead Life Lung Lung diseases Mediating Military Personnel Modeling Morbidity - disease rate Morphology Pathogenesis Pathogenicity Pathway Analysis Pathway interactions Peptide Hydrolases Peptides Population Predisposition Prevention Protein Isoforms Proteins Public Health Reducing Agents Regulation Rodent SWI1 Scaffolding Protein Serotyping Surface Symptoms Testing Therapeutic Therapeutic Agents Tight Junctions Transplantation Vaccines Variant Viral Virus Virus Diseases Virus Receptors Work adenovirus receptor airway epithelium design effective therapy extracellular gamma secretase immunosuppressed in vivo insight mortality novel novel therapeutic intervention novel therapeutics pathogen prevent prophylactic protein expression protein protein interaction receptor secretase tissue tropism

项目摘要

PROJECT SUMMARY/ABSTRACT Adenoviruses (AdV) are common human pathogens that cause typical cold symptoms in healthy indi- viduals, but can potentially progress to acute respiratory distress syndrome (ARDS) with up to 50% mortality, particularly in highly susceptible, immunosuppressed people, and new, potentially lethal variants continue to emerge each year. No therapeutic that specifically prevents or treats AdV infection exists and the development of novel treatments would prevent the morbidity and potentially mortality associated with AdV infection. The objective of this proposal is to determine the mechanism of action and anti-adenovirus efficacy of novel molecules that decrease apical Coxsackievirus and adenovirus receptor (CAREx8) protein expression. Our central hypothesis is that decoy peptides that block the interaction between MAGI-1 and CAREx8 destabi- lize apical CAREx8 protein in the airway to abrogate AdV entry and pathogenesis. We will test our hypothesis using polarized model epithelia with Dox-inducible CAREx8 expression, well-differentiated primary human and rodent airway epithelia to validate our findings, and the cotton rat model to evaluate wildtype AdV pathogenesis in immunocompetent and cyclophosphamide-immunosuppressed animals, with two specific aims: Aim 1: To elucidate the mechanism of MAGI-1 activating peptide and AdV triggered proteolytic degra- dation of CAREx8. Completion of this aim will allow the identification and development of novel and much needed targets and approaches to prevent the infection and spread of pathogenic wild-type AdV and, in the future, group B coxsackieviruses. Aim 2: To define the protection afforded by MAGI-1 PDZ1 binding peptides against wild type adenovi- rus infection in cotton rats. Completion of this aim will provide proof-of-principle that AdV infection can be thwarted by reducing its primary receptor and may save lives of severely infected or immunosuppressed indi- viduals. Overall impact: Understanding the mechanisms that regulate the expression and localization of CAREx8, and how this unique isoform mediates viral entry at the apical surface of a polarized epithelium is criti- cal for understanding viral spread, tissue tropism, and pathogenesis. The successful completion of the pro- posed aims will identify not only the cellular mechanisms regulating the expression of the apical adenovirus receptor but also mechanisms regulating viral binding and infection. This will establish the feasibility of thera- peutic agents that reduce the susceptibility of the airway epithelium to adenovirus infection and pathogenicity prior to infection and during an active infection in immunocompetent and immunosuppressed conditions. We ultimately expect the proposed aims to lead to novel anti-viral interventions that may also block other viruses that use CAR as a primary receptor, and provide insight into the regulation of other related viral receptors.

项目摘要/摘要腺病毒（ADV）是常见的人类病原体，在健康的健康中引起典型的冷症状 Viduals，但可能会发展为急性呼吸窘迫综合征（ARDS），死亡率高达50％，特别是在高度易感性的，免疫抑制的人和新的，可能致命的变体中继续每年出现。没有专门阻止或治疗ADV感染的治疗性新型治疗方法将防止与ADV感染相关的发病率和潜在的死亡率。该提案的目的是确定作用机理和抗腺病毒的疗效降低顶端Coxsackievievirus和腺病毒受体（CAREX8）蛋白表达的新型分子。我们的中心假设是，阻止Magi-1和Carex8 DeStabi-的相互作用的诱饵肽 Lize顶端Carex8蛋白在气道中消除ADV进入和发病机理。我们将检验我们的假设使用偏振模型上皮和DOX诱导的Carex8表达，分别差异化的原代人和啮齿动物气道上皮验证我们的发现和棉花大鼠模型以评估WildType Adv发病机理在免疫能力和环磷酰胺 - 免疫抑制的动物中，有两个特定的目的：目标1：阐明MAGI-1激活肽的机制，并触发了蛋白水解降解 Carex8。这个目标的完成将允许识别和发展小说和很多需要的目标和方法，以防止致病性野生型ADV的感染和传播，并在未来，B组Coxsackieviruses。目标2：定义MAGI-1 PDZ1结合肽对野生型Adenovi- 棉花大鼠的RUS感染。该目标的完成将提供原则上的证明，即ADV感染可能是通过减少其主要受体的挫败，并可以挽救严重感染或免疫抑制的生命 viduals。总体影响：了解调节表达和定位的机制 Carex8，以及这种独特的同工型如何介导两极分化上皮的顶端的病毒进入是批评的了解病毒蔓延，组织乳房和发病机理。成功完成提出的目标不仅会确定调节根尖腺病毒表达的细胞机制受体以及调节病毒结合和感染的机制。这将确定thera的可行性降低气道上皮对腺病毒感染和致病性的敏感性在感染之前和在免疫能力和免疫抑制条件下进行主动感染。我们最终期望拟议的旨在导致新型的抗病毒干预措施，这也可能阻止其他病毒该汽车用作主要受体，并深入了解其他相关病毒受体的调节。