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

• 批准号: 9750122
• 负责人: Douglas W Leaman
• 金额: $ 37.5万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 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/9750122
• 关键词: Acute; Adenovirus Infections; Adenoviruses; Adult Respiratory Distress Syndrome; Animals; Antiviral Agents; 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; human pathogen; immunosuppressed; in vivo; insight; mortality; novel; novel therapeutic intervention; novel therapeutics; prevent; prophylactic; protein expression; protein protein interaction; receptor; secretase; tissue tropism

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)是一种常见的人类病原体，可引起健康人群典型的感冒症状。 但有可能发展为急性呼吸窘迫综合征(ARDS)，死亡率高达50%， 尤其是在高度易感、免疫抑制的人群中，新的、潜在的致命变异继续存在 每年都会出现。目前还没有专门预防或治疗ADV感染的疗法存在和发展 新的治疗方法将防止与ADV感染相关的发病率和潜在死亡率。 本建议的目的是确定其作用机制和抗腺病毒的疗效。 降低顶端柯萨奇病毒和腺病毒受体(CAREx8)蛋白表达的新分子。 我们的中心假设是，阻断MAGI-1和CAREx8之间相互作用的诱骗多肽- Lize顶端CAREx8蛋白在气道中的表达，以消除ADV进入和发病机制。我们将检验我们的假设 使用具有Dox诱导的CAREx8表达的极化模型上皮细胞，高分化的原代和 用啮齿动物呼吸道上皮细胞来验证我们的发现，并用棉花大鼠模型来评价野生型ADV的致病作用 在免疫活性和环磷酰胺免疫抑制的动物中，有两个特定的目的： 目的1：阐明MAGI-1激活肽和ADV诱导的蛋白水解性变性的机制。 CAREx8.完成这一目标将允许识别和开发新的和许多 预防致病性野生型ADV感染和传播所需的目标和方法，在 未来，B组柯萨奇病毒。 目的2：确定MAGI-1 PDZ1结合肽对野生型腺病毒的保护作用。 棉鼠体内的RUS感染。完成这一目标将提供原则证据，证明ADV感染可以 通过减少其主要受体而受阻，并可能挽救严重感染或免疫抑制的患者的生命- 活人。 总体影响：了解调控表达和本地化的机制 CAREx8，以及这种独特的异构体如何介导病毒进入极化上皮的顶端表面是关键。 CAL，用于了解病毒传播、组织取向和发病机制。顺利完成PRO- 已提出的AIMS不仅将确定调节顶端腺病毒表达的细胞机制 不仅是受体，而且还有调节病毒结合和感染的机制。这将确立Thera的可行性-- 降低呼吸道上皮对腺病毒感染易感性和致病性的化疗药物 在感染之前和在免疫活性和免疫抑制条件下的活动性感染期间。我们 最终，预计拟议的目标将导致新的抗病毒干预措施，也可能阻止其他病毒 使用CAR作为主要受体，并为其他相关病毒受体的调控提供了洞察力。