An animal model for cytomegalovirus-induced pathology in the developing retina

发育中视网膜中巨细胞病毒诱导病理学的动物模型

• 批准号: 10559671
• 负责人: Christopher M Snyder
• 金额: $ 7.8万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559671
• 关键词: Adult; Age; Age related macular degeneration; Aging; Animal Model; Antibody Response; Architecture; Automobile Driving; Birth; Blood-Retinal Barrier; Brain; CD8-Positive T-Lymphocytes; Cell Compartmentation; Cell physiology; Cells; Child; Choroid; Choroidal Neovascularization; Chronic; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Retinitis; Data; Development; Disease; Exclusion; Eye; Eye Infections; Eye diseases; Foundations; Functional disorder; Future; Ganglion Cell Layer; Gene Expression Profile; Goals; Health; Hematopoietic; Herpesviridae; Histology; Human; Immune; Immune response; Immune system; Immunologic Surveillance; Immunologic Tests; Immunologics; Inbred BALB C Mice; Infant; Infection; Infiltration; Inflammation; Inner Nuclear Layer; Intervention; Kinetics; Life; Link; Long-Term Effects; Longevity; Macrophage; Macrophage Activation; Modeling; Mus; Myelogenous; Myeloid Cells; Neonatal; Neural Retina; Nuclear; Optic Nerve; Optical Coherence Tomography; Outcome; Pathologic; Pathology; Pattern; Persons; Retina; Role; Site; T-Lymphocyte; Testing; Time; Tissues; Viral; Viral Eye Infections; Virus; Virus Diseases; Virus Replication; Visual impairment; Western World; Work; cell type; chemokine; congenital cytomegalovirus; congenital infection; cytokine; experimental study; immune activation; immune cell infiltrate; in utero; latent infection; mouse model; neonatal infection; novel; novel therapeutics; novel vaccines; prevent; recruit; retinal damage

ABSTRACT Viral infections of the eye can cause severe damage and impair vision. Cytomegalovirus (CMV) is a herpesvirus that infects the eye and persists for life, causing problems across the life-span of the host. Importantly, CMV causes the most common congenital (in utero) infection in the western world, with vision impairment being one common outcome. However, the mechanisms of disease are unknown and no animal models exist to begin dissecting pathophysiology or developing interventions. Moreover, like all herpesviruses, CMV establishes a persistent/latent infection and provocative evidence suggests that chronic CMV carriage contributes to age- related macular degeneration (AMD) and choroidal neovascularization. These outcomes may be related to the persistent activation of macrophages by CMV and/or the constant immune surveillance of virus in the eye. Again, mechanisms are undefined. Thus, there is a critical need for animal models to define mechanisms and test interventions. Our preliminary data suggest that MCMV infection of newborn BALB/c mice results in infection of the retina, large numbers of infiltrating hematopoietic cells, and markedly disrupted retinal development with focal distortions in the inner and outer nuclear layers. To our knowledge, this is the first description of a mouse model for symptomatic congenital CMV infection of the eye. The purpose of this RO3 proposal is to characterize this new model and to directly compare the immediate and long-term outcomes of infections that occur early and later in life. Aim 1 will define the progression of viral infection, including the kinetics of infection and the cells that are infected, as well as differences between infection of newborn mice and adult mice. Aim 2 will define the immune infiltration of the retina, determine the changes in tissue transcriptional profile induced by infection, and test whether a viral chemokine is critical for initiating recruitment of hematopoietic cells and pathology. Aim 3 will determine the long-term effects of chronic MCMV carriage. These studies will provide a critical foundation for future work testing interventions and dissecting the mechanisms of CMV-induced disease in the presence of a functional, developing, immune system, and the long-term outcomes of such early-life infections.

摘要 眼睛的病毒感染会导致严重的损害和视力受损。巨细胞病毒（CMV）是一种疱疹病毒 感染眼睛并持续终生，在宿主的整个生命周期中引起问题。重要的是，CMV 导致西方世界最常见的先天性（子宫内）感染，视力障碍是其中之一 共同的结果。然而，疾病的机制是未知的，也没有动物模型存在开始 解剖病理生理学或开发干预措施。此外，像所有疱疹病毒一样，CMV建立了一个 持续/潜伏感染和挑衅性的证据表明，慢性CMV携带有助于年龄- 相关性黄斑变性（AMD）和脉络膜新生血管形成。这些结果可能与 巨噬细胞被CMV持续激活和/或眼睛中病毒的持续免疫监视。我再次重申， 机制尚未确定。因此，迫切需要动物模型来定义机制和测试， 干预措施。我们的初步数据表明，新生BALB/c小鼠MCMV感染导致 视网膜，大量浸润造血细胞，并明显破坏视网膜发育， 核内层和核外层的焦点畸变。据我们所知，这是第一次描述老鼠 有症状的眼睛先天性CMV感染的模型。本RO3提案的目的是描述 这一新模型，并直接比较早期发生的感染的即时和长期结果， 在以后的人生中。目的1将定义病毒感染的进展，包括感染的动力学和细胞， 以及新生小鼠和成年小鼠感染的差异。目标2将定义 视网膜的免疫浸润，确定由感染诱导的组织转录谱的变化，和 测试病毒趋化因子是否对启动造血细胞的募集和病理学至关重要。目标3 将决定慢性MCMV携带的长期影响。这些研究将提供一个关键的基础 为将来的工作测试干预措施和解剖机制CMV诱导的疾病的存在下， 一个功能性的，发育中的免疫系统，以及这种早期感染的长期结果。