Role of ABCG1 in Zika virus induced chorioretinal atrophy

项目摘要 最近在巴西爆发的寨卡病毒(ZIKV)出现了出人意料的严重 在以前的寨卡病毒暴发或其他相关疾病中没有观察到的神经表现 黄病毒。这促使世界卫生组织宣布全球进入公共卫生紧急状态 除了神经系统疾病外，ZIKV感染现在越来越多 与葡萄膜炎、急性黄斑病变、色素沉着等眼部并发症相关 视网膜病变和脉络膜视网膜萎缩。这些临床表现清楚地表明，黄斑部和 脉络膜视网膜疾病可显著影响感染ZIKV的婴儿和 成年人。然而，目前尚不清楚先天性眼部并发症是否直接导致 ZIKV或继发于小头畸形。由于视网膜是ZIKV在 眼，我们已经建立了ZIKV诱导的脉络膜视网膜萎缩的小鼠模型。我们发现 排列在血-视网膜屏障(BRB)和视网膜色素上皮(RPE)上的细胞高度 允许使用ZIKV。总而言之，这些发现使我们假设ZIKV获得了 通过BRB的眼睛。尽管ZIKV与ZIKV的其他成员之间关系密切 黄病毒科，如DENV、WNV和JEV，目前尚不清楚为什么只有ZIKV引起 先天性疾病及相关并发症。为了解决这个问题，我们比较了 ZIKV感染的RPE细胞的转录组与其他细胞的转录组特征 相关病毒。这导致了胆固醇膜转运蛋白Abcg1的鉴定， 作为ZIKV致病过程中特异参与的候选基因。作为支持，我们的 初步数据显示，对Abcg1活性的药理抑制可减弱ZIKV 在RPE细胞中复制。因此，这项研究的总体目标是 担忧。 就是确定分子 Abcg1促进RPE中病毒复制的机制并确定 Abcg1消融在ZIKV诱导的脉络膜视网膜萎缩病理生物学中的后果。至 为了实现这一目标，我们将追求两个具体目标：目标1是确定ZIKV是如何诱导的 Abcg1表达调控RPE中胆固醇合成/外排促进ZIKV复制 细胞。AIM-2旨在研究Abcg1在ZIKV诱导的ZIKV病理生物学中的作用 携带RPE特异性条件性基因敲除的Abcg1-BEST1Cre小鼠的脉络膜视网膜萎缩。 完成后，这些目标将阐明Abcg1在眼部寨卡病毒感染中的作用， 尤其是在脉络膜视网膜萎缩的发病机制中。鉴于ZIKV及其病毒的快速传播 对眼睛健康的影响，这项工作对药物的开发至关重要 治疗寨卡病毒感染，预防其并发症。

Project Summary The most recent outbreak of Zika Virus (ZIKV) in Brazil has presented with unexpectedly severe neurological manifestations, which were not observed in prior outbreaks of ZIKV or other related flaviviruses. This prompted the WHO to declare a public health emergency of international In addition to neurologic disorders, ZIKV infection is now being increasingly associated with ocular complications such as uveitis, acute maculopathy, pigmentory retinopathy, and chorioretinal atrophy. These clinical findings make it clear that macular and chorioretinal disease can significantly impact visual outcomes in ZIKV-infected infants and adults. However, it is not yet clear whether congenital ocular complications are directly caused by ZIKV or are secondary to microcephaly. As the retina is the primary target of ZIKV in the eye, we have developed a mouse model of ZIKV-induced chorioretinal atrophy. We found that cells lining the blood-retinal barrier (BRB), the retinal pigment epithelium (RPE), are highly permissive to ZIKV. Collectively, these findings led us to postulate that ZIKV gains access to the eye by via BRB. Despite the close relationship between ZIKV and other members of the flaviviridae family, such as DENV, WNV, and JEV, it remains unclear why only ZIKV causes congenital disorders and associated complications. To address this question , we compared the transcriptome of ZIKV-infected RPE cells with the transcriptome signatures of the other related viruses. This led to the identification of ABCG1, a cholesterol membrane transporter, as a candidate gene that is specifically involved in the pathogenesis of ZIKV. In support, our preliminary data show that pharmacological inhibition of ABCG1 activity attenuated ZIKV replication in RPE cells. Thus, the overall objective of this study concern. is to determine molecular mechanisms by which ABCG1 promotes viral replication in RPE and determine the consequences of ABCG1 ablation in the pathobiology of ZIKV-induced chorioretinal atrophy. To achieve this goal, we will pursue two specific aims: Aim-1 is to determine how ZIKV-induced ABCG1 expression modulates cholesterol synthesis/efflux to promote ZIKV replication in RPE cells. Aim-2 is designed to investigate the role of ABCG1 in the pathobiology of ZIKV-induced chorioretinal atrophy in ABCG1-BEST1Cre mice harboring an RPE-specific conditional knockout. Upon completion, these aims will elucidate the role of ABCG1 in ocular ZIKV infection, particularly in the pathogenesis of chorioretinal atrophy. Given the rapid spread of ZIKV and its impact on ocular health, this work is of paramount importance for the development of drugs to treat ZIKV infection and prevent its complications.