Biosciences Institute, Faculty of Medical Sciences, Newcastle University, UK.
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, UK; Microscopy Centre and Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, Italy.
Ocul Surf. 2021 Jan;19:190-200. doi: 10.1016/j.jtos.2020.05.013. Epub 2020 Jun 3.
The high infection rate of SARS-CoV-2 necessitates the need for multiple studies identifying the molecular mechanisms that facilitate the viral entry and propagation. Currently the potential extra-respiratory transmission routes of SARS-CoV-2 remain unclear.
Using single-cell RNA Seq and ATAC-Seq datasets and immunohistochemical analysis, we investigated SARS-CoV-2 tropism in the embryonic, fetal and adult human ocular surface.
The co-expression of ACE2 receptor and entry protease TMPRSS2 was detected in the human adult conjunctival, limbal and corneal epithelium, but not in the embryonic and fetal ocular surface up to 21 post conception weeks. These expression patterns were corroborated by the single cell ATAC-Seq data, which revealed a permissive chromatin in ACE2 and TMPRSS2 loci in the adult conjunctival, limbal and corneal epithelium. Co-expression of ACE2 and TMPRSS2 was strongly detected in the superficial limbal, corneal and conjunctival epithelium, implicating these as target entry cells for SARS-CoV-2 in the ocular surface. Strikingly, we also identified the key pro-inflammatory signals TNF, NFKβ and IFNG as upstream regulators of the transcriptional profile of ACE2TMPRSS2 cells in the superficial conjunctival epithelium, suggesting that SARS-CoV-2 may utilise inflammatory driven upregulation of ACE2 and TMPRSS2 expression to enhance infection in ocular surface.
Together our data indicate that the human ocular surface epithelium provides an additional entry portal for SARS-CoV-2, which may exploit inflammatory driven upregulation of ACE2 and TMPRSS2 entry factors to enhance infection.
SARS-CoV-2 的高感染率需要多项研究来确定促进病毒进入和传播的分子机制。目前，SARS-CoV-2 潜在的非呼吸道传播途径尚不清楚。
使用单细胞 RNA Seq 和 ATAC-Seq 数据集和免疫组织化学分析，我们研究了 SARS-CoV-2 在人眼表面的胚胎、胎儿和成人中的嗜性。
在成人结膜、角膜缘和角膜上皮中检测到 ACE2 受体和进入蛋白酶 TMPRSS2 的共表达，但在胚胎和胎儿眼表面直至妊娠 21 周后未检测到。单细胞 ATAC-Seq 数据证实了这些表达模式，该数据揭示了成人结膜、角膜缘和角膜上皮中 ACE2 和 TMPRSS2 基因座的可允许染色质。ACE2 和 TMPRSS2 的共表达在浅层角膜缘、角膜和结膜上皮中强烈检测到，这表明这些细胞是 SARS-CoV-2 在眼表面的靶进入细胞。引人注目的是，我们还鉴定出关键的促炎信号 TNF、NFKβ 和 IFNG 作为浅层结膜上皮中 ACE2TMPRSS2 细胞转录谱的上游调节剂，表明 SARS-CoV-2 可能利用炎症驱动的 ACE2 和 TMPRSS2 表达上调来增强眼表面的感染。
我们的数据表明，人眼表面上皮为 SARS-CoV-2 提供了额外的进入门户，它可能利用炎症驱动的 ACE2 和 TMPRSS2 进入因子的上调来增强感染。
