Immunopathogenesis of Adenovirus Keratitis

腺病毒角膜炎的免疫发病机制

基本信息

批准号：
8183473
负责人：
James Chodosh
金额：
$ 39.25万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8183473
关键词：
3-Dimensional Acute Address Adenovirus Infections Adenoviruses Adrenal Cortex Hormones Affect Binding Blindness Blurred vision Bone Marrow CCL2 gene CXC Chemokines CXCL1 gene Capsid Capsid Proteins Cells Clinical Conjunctivitis Cornea Corneal Stroma DNA Dendritic Cells Differentiation Antigens Disease model Enzyme-Linked Immunosorbent Assay Epidemic Keratoconjunctivitis Epithelial Esthesia Event Exposure to Eye Eye Infections Fluorescence Foreign Bodies Funding Future Goals Human Human Adenoviruses IL8 gene ITGAM gene ITGAX gene Immune response In Vitro Individual Infection Inflammation Inflammatory Interleukin-6 Investigation Keratitis Keratoconjunctivitis Label Laboratories Life Literature Mediator of activation protein Microscopy Modeling Molecular Molecular Profiling Mus Natural Immunity Nuclear Pain Patients Pattern Pattern recognition receptor Phenotype Photophobia Process Public Health Recurrence Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Stromal Cells Testing Tissues Toll-like receptors Transgenic Mice Viral Viral Pathogenesis Virus Diseases Vision research Visual impairment Work base cell type chemokine cytokine facsimile in vitro Model in vivo migration mouse model mouse toll-like receptor 9 neutrophil novel ocular surface pathogen prevent research study response three-dimensional modeling two-photon viral DNA

项目摘要

DESCRIPTION (provided by applicant): Epidemic keratoconjunctivitis is caused by human adenovirus species D (HAdV-D) types 8, 19, and 37, and more recently also 53 and 54. The clinical manifestations of this infection include severe membranous conjunctivitis and epithelial keratitis, followed by multifocal subepithelial (stromal) corneal infiltrates that cause photophobia and reduced vision and may persist for months to years. Previous studies focused on cellular and nuclear signaling events that led to expression of proinflammatory mediators such as CXCL1 (mouse), CXCL8 (human), and CCL2 in the corneal stroma. However, recent work by our laboratory using the mouse adenovirus keratitis model we developed and characterized in the last funding cycle resulted in novel observations regarding specific cytokine expression signatures associated with different pathogen associated molecular patterns presented to resident corneal stromal cells. Based on these observations, we propose that stromal inflammation following corneal adenovirus infection represents the summation of specific cytokine responses to infection by phenotypically distinct cell types in the corneal stroma. Our proposed study of the specific mechanisms for response of corneal stromal bone marrow derived cells to distinct adenovirus associated molecular patterns will be unique. In addition, we will employ for these studies a highly novel three dimensional model of tissue inflammation, the human corneal facsimile. Our specific aims to accomplish our goal are to test the following hypotheses: 1) adenoviruses infect bone marrow derived cells in the corneal stroma, 2) adenoviruses induce CXCL-1/8 chemokine expression in the corneal stroma through a molecular interaction between viral capsid protein and keratocytes and 3) adenoviruses induce CCL2 and IL-6 expression in the corneal stroma through a molecular interaction between viral DNA and dendritic cells. These studies will utilize both the mouse model of adenovirus keratitis and the human corneal facsimile model, and will uniquely test cellular and molecular mechanisms of innate immunity in a disease model of adenovirus infection. As adenoviruses represent the most common cause of eye infections, this proposal will address a major public health concern. PUBLIC HEALTH RELEVANCE: Ocular surface infection by adenoviruses represents the most common type of eye infection, and affected patients suffer considerably from pain and blurred vision when the cornea is involved. However, there is at present no specific therapy against adenovirus infections or the ocular inflammation that follows. Corticosteroids represent the only available treatment for adenovirus keratitis, but can be associated with unwanted effects, including prolonged adenovirus replication. This proposal directly addresses the mechanism of corneal innate immune responses to adenovirus infection of the cornea, specifically the interactions between specific pathogen associated molecular patterns on the adenovirus and resident bone marrow derived cells in the corneal stroma. This work will inform a mechanistic molecular approach to future translational therapies for adenovirus induced corneal inflammation.

DESCRIPTION (provided by applicant): Epidemic keratoconjunctivitis is caused by human adenovirus species D (HAdV-D) types 8, 19, and 37, and more recently also 53 and 54. The clinical manifestations of this infection include severe membranous conjunctivitis and epithelial keratitis, followed by multifocal subepithelial (stromal) corneal infiltrates that cause photophobia and reduced vision并可能持续数月到几年。先前的研究集中在细胞和核信号传导事件上，导致角膜基质中促炎性介质（如CXCL1（小鼠），CXCL8（人）和CCL2）的表达。但是，我们实验室使用小鼠腺病毒角膜炎模型的最新工作，我们在上一个融资周期中开发和表征了对与驻留在居民角膜基质细胞的不同病原体相关的分子模式相关的特定细胞因子表达特征的新观察结果。基于这些观察结果，我们提出角膜腺病毒感染后的基质炎症代表了角膜基质中表型不同细胞类型对特定细胞因子对感染的特定细胞因子反应的总结。我们对角膜基质骨髓对不同腺病毒相关分子模式反应的特定机制的拟议研究是独一无二的。此外，我们将在这些研究中采用高度新颖的组织炎症三维模型，即人的角膜传真。我们实现目标的具体目的是测试以下假设：1）腺病毒感染角膜基质中的骨髓衍生的细胞，2）腺病毒在角膜基质中诱导CXCL-1/8趋化因子在角膜基质中通过分子相互作用在病毒蛋白质和基质中的表达之间以及3）adeneal cccliruses cccliruse in ccclomar scression in Moleccular stroma诱导了CXCL-1/8趋化因子。病毒DNA和树突状细胞之间的分子相互作用。这些研究将同时利用腺病毒角膜炎的小鼠模型和人类角膜相关模型，并将在腺病毒感染疾病模型中独特地测试先天免疫的细胞和分子机制。由于腺病毒代表了眼感染的最常见原因，因此该提案将解决一个主要的公共卫生问题。公共卫生相关性：腺病毒的眼部表面感染是最常见的眼部感染类型，当涉及角膜时，受到疼痛和视力模糊的影响。但是，目前尚无针对腺病毒感染或随后的眼部炎症的特定疗法。皮质类固醇是腺病毒角膜炎的唯一可用治疗方法，但可能与不良作用有关，包括长时间的腺病毒复制。该提案直接解决了角膜对角膜腺病毒感染的固有免疫反应的机制，特别是腺病毒上特定病原体相关的分子模式与角膜基质中常驻骨髓细胞之间的相互作用。这项工作将为腺病毒诱导的角膜炎症的未来转化疗法提供机械性分子方法。