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.

抽象的 眼睛的病毒感染会造成严重损害并损害视力。巨细胞病毒 (CMV) 是一种疱疹病毒 它会感染眼睛并终生持续存在，从而在宿主的整个生命周期中造成问题。重要的是，巨细胞病毒 导致西方世界最常见的先天性（子宫内）感染，其中视力障碍是其中之一 共同的结果。然而，疾病的机制尚不清楚，也没有动物模型可以开始 剖析病理生理学或制定干预措施。此外，像所有疱疹病毒一样，CMV 建立了 持续/潜伏感染和刺激性证据表明，慢性 CMV 携带会导致年龄增长 相关黄斑变性（AMD）和脉络膜新生血管。这些结果可能与 CMV 持续激活巨噬细胞和/或眼睛中病毒的持续免疫监视。再次， 机制未定义。因此，迫切需要动物模型来定义机制并进行测试 干预措施。我们的初步数据表明，新生 BALB/c 小鼠的 MCMV 感染导致感染 视网膜，大量浸润造血细胞，并明显破坏视网膜发育 内核层和外核层的焦点扭曲。据我们所知，这是对鼠标的第一个描述 有症状的先天性巨细胞病毒眼部感染模型。 RO3 提案的目的是描述 这种新模型可以直接比较早期和长期感染的近期和长期结果 在以后的生活中。目标 1 将定义病毒感染的进展，包括感染动力学和感染细胞 是否被感染，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，确定感染引起的组织转录谱的变化，以及 测试病毒趋化因子对于启动造血细胞和病理学是否至关重要。目标 3 将决定慢性 MCMV 携带的长期影响。这些研究将为 为未来的工作测试干预措施并剖析巨细胞病毒诱发疾病的机制 功能性、发育中的免疫系统，以及此类早期感染的长期后果。