Role of Cell Integrins in Adenoviral Conjunctivitis

细胞整合素在腺病毒结膜炎中的作用

基本信息

批准号：
7643851
负责人：
Glen R Nemerow
金额：
$ 41.45万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7643851
关键词：
Acute Adenoviruses Animal Model Antiviral Agents Binding Binding Sites Biochemical CAR receptor CD46 Antigen Cells Complement Complex Conjunctivitis Cryoelectron Microscopy Development Disease Drug or chemical Tissue Distribution Epidemic Keratoconjunctivitis Epithelial Cells Evaluation Extracellular Domain Eye Eye Infections Family member Fiber Funding Gene Delivery Human Human Adenoviruses Immune response Immunity In Vitro Infection Inflammatory Integrins Interleukin-12 Kinetics Knowledge Ligand Binding Link Location Mediating Molecular Molecular Genetics Mutagenesis Natural Immunity Oligosaccharides Pathogenesis Pathway interactions Play Process Proteins Receptor Cell Regulation Resolution Role Serotyping Structure Subgroup Surface Plasmon Resonance Techniques Transgenic Mice Tropism Viral Viral Eye Infections Virus X ray diffraction analysis X-Ray Diffraction base cytokine design gastrointestinal genetic regulatory protein improved in vivo insight microbial mouse model novel pathogen prevent receptor respiratory stoichiometry three dimensional structure vector

项目摘要

Adenoviruses are associated with acute respiratory, gastrointestinal, and ocular infections. While several different Ad types can cause eye infections (viral pink eye), only subgroup D Ad types (Ad37, Ad19 and Ad8) are associated with a particularly severe ocular disease known as epidemic keratoconjunctivitis (EKC). Until recently, knowledge of subgroup D host cell tropism was quite limited. We discovered that the relatively short and inflexible Ad37 fiber protein restricts virus interactions with CAR, the cell receptor used by most other Ad types. To overcome this limitation, Ad37 uses a distinct cell receptor, CD46 (also known as Membrane Cofactor Protein) to bind to host cells. In this proposal, we will investigate the precise molecular interactions involved in Ad37 binding to CD46 using biochemical and molecular genetic approaches. Complementary studies will analyze the three dimensional structure of Ad-CD46 complexes at moderate to high resolution using cryoelectron microscopy or X-ray diffraction. CD46 has been usurped by diverse microbial pathogens and thus, this receptor may serve important functions beyond host cell recognition. In this regard, our recent studies showed that Ad37 downregulates expression of interleukin-12 (IL-12). This key inflammatory cytokine links the innate and adaptive immune response and therefore may play a crucial role in viral clearance. In further studies, we will examine the mechanisms involved in Ad-mediated cytokine regulation. We will also analyze whether CD46 expression in relevant cell and animal models enhances Ad37 infection in vitro and in vivo. These studies should increase our understanding of Ad tropism and ocular pathogenesis. They may also provide insights for the development of novel antiviral agents as well as improved gene delivery vectors.

腺病毒与急性呼吸道、胃肠道和眼部感染有关。虽然几种不同的 Ad 类型可引起眼部感染（病毒性红眼病），但只有 D 亚组 Ad 类型（Ad37、Ad19 和 Ad8）与一种特别严重的眼部疾病（称为流行性角结膜炎 (EKC)）相关。直到最近，对 D 亚群宿主细胞趋向性的了解还相当有限。我们发现相对较短且不灵活的 Ad37 纤维蛋白限制了病毒与 CAR 的相互作用，CAR 是大多数其他 Ad 类型使用的细胞受体。为了克服这一限制，Ad37 使用独特的细胞受体 CD46（也称为膜辅因子蛋白）来与宿主细胞结合。在本提案中，我们将使用生化和分子遗传学方法研究 Ad37 与 CD46 结合所涉及的精确分子相互作用。补充研究将使用冷冻电子显微镜或 X 射线衍射以中高分辨率分析 Ad-CD46 复合物的三维结构。 CD46 已被多种微生物病原体侵占，因此，该受体可能发挥宿主细胞识别之外的重要功能。在这方面，我们最近的研究表明Ad37下调白细胞介素12（IL-12）的表达。这种关键的炎症细胞因子将先天性和适应性免疫反应联系起来，因此可能在病毒清除中发挥至关重要的作用。在进一步的研究中，我们将研究 Ad 介导的细胞因子调节所涉及的机制。我们还将分析相关细胞和动物模型中CD46的表达是否增强Ad37在体外和体内的感染。这些研究应该会增加我们对Ad向性和眼部发病机制的了解。它们还可以为新型抗病毒药物的开发以及改进的基因传递载体提供见解。