Assessing SARS-CoV-2 entry, replication and prevention in a primary human conjunctival cell model and organ cultured cornea/conjunctiva.

评估原代人类结膜细胞模型和器官培养角膜/结膜中 SARS-CoV-2 的进入、复制和预防。

• 批准号: BB/V01126X/1
• 负责人: Majlinda Lako
• 金额: $ 24.91万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV01126X%2F1
• 关键词: Assessing; SARS; CoV; entry; replication

The SARS-CoV-2 virus, which has caused the COVID-19 pandemic, is highly infectious and predominantly transmitted through respiratory droplets. To enter the host cell SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a cellular receptor and the transmembrane protease serine type 2 (TMPRSS2) for fusion of viral and cellular membranes. The ocular surface epithelia, conjunctiva and cornea, represent an additional mucosal surface, which can be exposed to respiratory droplets. Several published reports have shown that SARS-CoV-2 can cause conjunctivitis, either as an early sign of infection, or during hospitalization for severe COVID-19 disease. In a recent study of 38 COVID-19 patients, 31.6% had conjunctivitis with 16.7% of these testing positive for SARS-CoV-2 from conjunctival and nasopharyngeal swabs. There is evidence that numerous properties allow the eye to serve as a potential site of virus replication and a gateway for the establishment of respiratory infection, through the nasolacrimal system linking the ocular and respiratory tissues. Our recent data shows co-expression of ACE2 and TMPRSS2 in human superficial conjunctival, limbal and corneal epithelium, suggesting a potential extra-respiratory transmission route of SARS-CoV-2 via the ocular surface. In this proposal we will use human ex vivo differentiated conjunctival and corneal epithelium and organ cultured cornea/conjunctiva as pre-clinical tools to study the entry of SARS-CoV-2 via the ocular surface and to develop effective diagnostic, prophylactics and treatments in the fight against COVID-19. We envisage that proof-of-concept studies developed herein will lead not only to development of eye drops, but also nasal sprays and mouth washes, to provide the much-needed therapies in time of pandemics.

引起COVID-19大流行的SARS-CoV-2病毒具有高度传染性，主要通过呼吸道飞沫传播。为了进入宿主细胞，SARS-CoV-2使用血管紧张素转换酶2（ACE 2）作为细胞受体，并使用跨膜蛋白酶丝氨酸2型（TMPRSS 2）来融合病毒和细胞膜。眼表上皮细胞、结膜和角膜代表另外的粘膜表面，其可暴露于呼吸道飞沫。几份已发表的报告显示，SARS-CoV-2可导致结膜炎，无论是作为感染的早期迹象，还是在严重COVID-19疾病住院期间。在最近对38名COVID-19患者的研究中，31.6%的人患有结膜炎，其中16.7%的人在结膜和鼻咽拭子中检测出SARS-CoV-2阳性。有证据表明，通过连接眼部和呼吸道组织的鼻泪管系统，许多特性使眼睛成为病毒复制的潜在场所和建立呼吸道感染的门户。我们最近的数据显示ACE 2和TMPRSS 2在人浅层结膜、角膜缘和角膜上皮中共表达，表明SARS-CoV-2通过眼表的潜在呼吸道外传播途径。在本提案中，我们将使用人离体分化的结膜和角膜上皮以及器官培养的角膜/结膜作为临床前工具，以研究SARS-CoV-2通过眼表的进入，并开发有效的诊断，药物和治疗方法，以对抗COVID-19。我们设想，在此开发的概念验证研究将不仅导致滴眼剂的开发，而且还导致鼻喷雾剂和漱口剂的开发，以在流行病发生时提供急需的治疗。

项目成果

Direct transcriptomic comparison of xenobiotic metabolism and toxicity pathway induction of airway epithelium models at an air-liquid interface generated from induced pluripotent stem cells and primary bronchial epithelial cells.

• DOI: 10.1007/s10565-022-09726-0
• 发表时间: 2023-02
• 期刊: Cell biology and toxicology
• 影响因子: 6.1

Understanding Ocular Surface Inflammation in Tears Before and After Autologous Cultivated Limbal Epithelial Stem Cell Transplantation.

• DOI: 10.1007/s40123-023-00656-6
• 发表时间: 2023-04
• 期刊: OPHTHALMOLOGY AND THERAPY
• 影响因子: 3.3
• 作者: Figueiredo, Gustavo S.;Hogg, Jeffry;Okonkwo, Arthur;Baylis, Oliver J.;Berry, Monica;Ali, Simi;Lako, Majlinda;Figueiredo, Francisco C.
• 通讯作者: Figueiredo, Francisco C.

SARS-CoV-2 infects an upper airway model derived from induced pluripotent stem cells.

• DOI: 10.1002/stem.3422
• 发表时间: 2021-10
• 期刊: Stem cells (Dayton, Ohio)
• 作者: Djidrovski I;Georgiou M;Hughes GL;Patterson EI;Casas-Sanchez A;Pennington SH;Biagini GA;Moya-Molina M;van den Bor J;Smit MJ;Chung G;Lako M;Armstrong L
• 通讯作者: Armstrong L

In the eye of the storm: SARS-CoV-2 infection and replication at the ocular surface?

• DOI: 10.1002/sctm.20-0543
• 发表时间: 2021-07
• 期刊: Stem cells translational medicine
• 影响因子: 6
• 作者: Armstrong L;Collin J;Mostafa I;Queen R;Figueiredo FC;Lako M
• 通讯作者: Lako M

Referral Patterns of Patients with Limbal Stem Cell Deficiency to a Specialized Tertiary Center in the United Kingdom.

• DOI: 10.1007/s40123-021-00349-y
• 发表时间: 2021-09
• 期刊: Ophthalmology and therapy
• 影响因子: 3.3
• 作者: Cartes C;Lako M;Figueiredo FC
• 通讯作者: Figueiredo FC