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

基本信息

批准号：
10432947
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
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432947
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 CD8B1 gene Cell Compartmentation Cell physiology Cells Child Choroid Choroidal Neovascularization Chronic Cytomegalovirus Cytomegalovirus Infections Data Development Disease 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 Activation Modeling Murid herpesvirus 1 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 Tumor-infiltrating immune cells 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 in utero latent persistent infection macrophage mouse model neonatal infection novel novel therapeutics novel vaccines prevent recruit retinal damage young adult

项目摘要

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导致严重损害并损害视力。巨细胞病毒（CMV）是疱疹病毒这会感染眼睛，并持续生命，从而在宿主的生命中引起问题。重要的是，CMV 引起西方世界中最常见的先天性（子宫内感染），视力障碍是一种共同的结果。但是，疾病的机制尚不清楚，没有动物模型开始剖析病理生理或发展干预措施。而且，像所有疱疹病毒一样，CMV建立了一个持续/潜在的感染和挑衅性证据表明，慢性CMV运输有助于年龄相关的黄斑变性（AMD）和脉络膜新生血管形成。这些结果可能与 CMV和/或眼睛中病毒持续的免疫监测对巨噬细胞的持续激活。再次，机制是不确定的。因此，动物模型的迫切需要定义机制和测试干预措施。我们的初步数据表明，新生儿BALB/C小鼠的MCMV感染导致感染视网膜，大量浸润的造血细胞，并明显破坏了视网膜发育内部和外核层中的局灶性畸变。据我们所知，这是鼠标的第一个描述有症状的先天性CMV感染的模型。该RO3建议的目的是表征这个新模型，并直接比较早期发生的感染的直接和长期结果后来生活。 AIM 1将定义病毒感染的进展，包括感染的动力学和细胞被感染，以及新生小鼠和成年小鼠的感染之间的差异。 AIM 2将定义视网膜的免疫浸润，确定感染引起的组织转录特征的变化，并确定测试病毒趋化因子对于启动造血细胞和病理的募集至关重要。目标3 将确定慢性MCMV运输的长期影响。这些研究将为重要的基础提供重要的基础用于未来的工作测试干预措施，并在存在下剖析CMV诱导的疾病的机制一种功能性，发展，免疫系统以及这种早期感染的长期结局。