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

摘要 眼睛的病毒感染会造成严重的损害和视力损害。巨细胞病毒是一种疱疹病毒。 它会感染眼睛并持续一生，在宿主的整个生命周期内都会造成问题。重要的是，CMV 导致西方世界最常见的先天性(宫内)感染，视力障碍是其中之一 常见的结果。然而，疾病的机制尚不清楚，也没有动物模型可以开始。 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建立了一种 持续/潜伏感染和挑衅性证据表明，慢性CMV携带者与年龄有关- 相关性黄斑变性(AMD)和脉络膜新生血管。这些结果可能与 巨细胞病毒对巨噬细胞的持续激活和/或眼睛内病毒的持续免疫监视。再说一遍， 机制是不确定的。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小鼠感染MCMV会导致 视网膜，大量渗入的造血细胞，并显著扰乱视网膜的发育 核内层和核外层的焦点扭曲。据我们所知，这是对老鼠的第一次描述 症状性先天性眼巨细胞病毒感染模型。该R03提案目的是描述 这一新模型并直接比较早期和长期感染的直接和长期结果 在以后的生活中。目标1将定义病毒感染的进展，包括感染的动力学和 以及新生小鼠感染和成年小鼠感染之间的差异。目标2将定义 视网膜的免疫渗透，决定感染引起的组织转录谱的变化，以及 检测病毒趋化因子是否对启动造血细胞募集和病理起关键作用。目标3 将决定慢性MCMV携带者的长期影响。这些研究将提供一个重要的基础 为了未来的工作，测试干预措施和解剖巨细胞病毒诱导的疾病的机制 一种功能性的、发育中的免疫系统，以及这种早期感染的长期后果。

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.