Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes.
Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes.
复制标题
寨卡病毒感染小梁网并引起小鼠眼睛小梁炎和青光眼病理。
DOI：
10.1128/msphere.00173-19
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发表时间：
2019
期刊：
影响因子：
4.8
通讯作者：
Kumar,Ashok
中科院分区：
文献类型：
--
作者：
Singh,PawanKumar;Kasetti,RameshB;Zode,GulabS;Goyal,Anju;Juzych,MarkS;Kumar,Ashok
妊娠期间感染寨卡病毒（ZIKV）会导致毁灭性的胎儿结局，包括神经系统（小头畸形）和眼部病变，如视网膜病变、视神经异常、脉络膜视网膜萎缩和先天性青光眼。只有临床病例报告将ZIKV感染与青光眼（一种主要的致盲性眼病）联系起来。在本研究中，我们使用体外和体内实验模型研究了ZIKV在青光眼病理生理学中的作用。我们表明，人原代小梁网（Pr. TM）细胞以及人GTM 3细胞系允许ZIKV感染。ZIKV在Pr. TM细胞中诱导表达模式识别受体（TLR 2、TLR 3和RIG-I）、细胞因子/趋化因子（TNF-α、IL-1β、CCL 5和CXCL 10）、干扰素（IFN-α2、IFN-β1和IFN-γ）和干扰素刺激基因（ISG 15和OAS 2）的各种基因的转录。IFNAR 1-/-和野生型（WT）小鼠眼睛中的ZIKV感染导致眼内压（IOP）升高和脉络膜视网膜萎缩的发展。ZIKV的前房（AC）接种引起虹膜角膜角和TM中的感染性，导致小鼠眼中TM细胞的死亡。此外，感染眼的眼前节组织表现出炎症介质和干扰素的表达增加。此外，IFNAR 1 −/−小鼠中的ZIKV感染导致视网膜神经节细胞（RGC）死亡和丢失，与视神经感染和顺行轴突运输中断一致。由于我们的研究和其他实验性青光眼模型中的青光眼病理学相似，ZIKV感染可用于研究青光眼的感染性触发因素，目前这是一个研究不足的领域。重要的是，由于ZIKV感染导致的眼部并发症仍然是一个主要的公共卫生问题，因为它们能够导致视力障碍或失明。大多数先前的研究已经显示ZIKV诱导的眼后段病变（即，视网膜）。然而，来自受影响国家的一些最近的临床报告强调了ZIKV在影响眼前节和引起先天性青光眼方面的重要性。由于青光眼是全球第二大致盲原因，因此研究ZIKV感染引起青光眼以确定治疗干预的潜在靶点是必要的。在这项研究中，我们发现ZIKV允许感染人TM细胞并引起引起小梁炎的炎症反应。使用小鼠模型，我们证明了ZIKV感染导致更高的IOP、增加的RGC损失和视神经异常，这是青光眼的经典标志。总的来说，我们的研究为眼部ZIKV感染导致青光眼病理提供了新的见解。
Zika virus (ZIKV) infection during pregnancy leads to devastating fetal outcomes, including neurological (microcephaly) and ocular pathologies such as retinal lesions, optic nerve abnormalities, chorioretinal atrophy, and congenital glaucoma. Only clinical case reports have linked ZIKV infection to causing glaucoma, a major blinding eye disease. In the present study, we have investigated the role of ZIKV in glaucoma pathophysiology usingin vitroandin vivoexperimental models. We showed that human primary trabecular meshwork (Pr. TM) cells, as well as a human GTM3 cell line, were permissive to ZIKV infection. ZIKV induced the transcription of various genes expressing pattern recognition receptors (TLR2,TLR3, andRIG-I), cytokines/chemokines (TNF-α,IL-1β,CCL5, andCXCL10), interferons (IFN-α2,IFN-β1, andIFN-γ), and interferon-stimulated genes (ISG15andOAS2) in Pr. TM cells. ZIKV infection in IFNAR1−/−and wild-type (WT) mouse eyes resulted in increased intraocular pressure (IOP) and the development of chorioretinal atrophy. Anterior chamber (AC) inoculation of ZIKV caused infectivity in iridocorneal angle and TM, leading to the death of TM cells in the mouse eyes. Moreover, anterior segment tissue of infected eyes exhibited increased expression of inflammatory mediators and interferons. Furthermore, ZIKV infection in IFNAR1−/−mice resulted in retinal ganglion cell (RGC) death and loss, coinciding with optic nerve infectivity and disruption of anterograde axonal transport. Because of similarity in glaucomatous pathologies in our study and other experimental glaucoma models, ZIKV infection can be used to study infectious triggers of glaucoma, currently an understudied area of investigation.IMPORTANCEOcular complications due to ZIKV infection remains a major public health concern because of their ability to cause visual impairment or blindness. Most of the previous studies have shown ZIKV-induced ocular pathology in the posterior segment (i.e., retina) of the eye. However, some recent clinical reports from affected countries highlighted the importance of ZIKV in affecting the anterior segment of the eye and causing congenital glaucoma. Because glaucoma is the second leading cause of blindness worldwide, it is imperative to study ZIKV infection in causing glaucoma to identify potential targets for therapeutic intervention. In this study, we discovered that ZIKV permissively infects human TM cells and evokes inflammatory responses causing trabeculitis. Using a mouse model, we demonstrated that ZIKV infection resulted in higher IOP, increased RGC loss, and optic nerve abnormalities, the classical hallmarks of glaucoma. Collectively, our study provides new insights into ocular ZIKV infection resulting in glaucomatous pathology.