Hultgren Nan W, Petcherski Anton, Torriano Simona, Komirisetty Ravikiran, Sharma Madhav, Zhou Tianli, Burgess Barry L, Ngo Jennifer, Osto Corey, Shabane Byourak, Shirihai Orian S, Kelesidis Theodoros, Williams David S
Department of Ophthalmology and Stein Eye Institute, University of California, Los Angeles, CA 90095, USA.
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
PNAS Nexus. 2024 Dec 3;3(12):pgae500. doi: 10.1093/pnasnexus/pgae500. eCollection 2024 Dec.
As the SARS-CoV-2 coronavirus continues to evolve and infect the global population, many individuals are likely to suffer from post-acute sequelae of SARS-CoV-2 infection (PASC). Manifestations of PASC include vision symptoms, but little is known about the ability of SARS-CoV-2 to infect and impact the retinal cells. Here, we demonstrate that SARS-CoV-2 can infect and perturb the retinal pigment epithelium (RPE) in vivo, after intranasal inoculation of a transgenic mouse model of SARS-CoV-2 infection, and in cell culture. Separate lentiviral studies showed that SARS-CoV-2 Spike protein mediates viral entry and replication in RPE cells, while the Envelope and ORF3a proteins induce morphological changes. Infection with major variants of SARS-CoV-2 compromised the RPE barrier function and phagocytic capacity. It also caused complement activation and production of cytokines and chemokines, resulting in an inflammatory response that spread across the RPE layer. This inflammatory signature has similarities to that associated with the onset of age-related macular degeneration (AMD), a major cause of human blindness, resulting from RPE pathology that eventually leads to photoreceptor cell loss. Thus, our findings suggest that post-acute sequelae of SARS-CoV-2 infection of the RPE may have long-term implications for vision, perhaps comparable to the increased occurrence of AMD found among individuals infected by HIV, but with greater public health consequences due to the much larger number of SARS-CoV-2 infections.
随着严重急性呼吸综合征冠状病毒2（SARS-CoV-2）持续演变并感染全球人群，许多人可能会患上SARS-CoV-2感染的急性后遗症（PASC）。PASC的表现包括视觉症状，但对于SARS-CoV-2感染和影响视网膜细胞的能力知之甚少。在此，我们证明，在鼻内接种SARS-CoV-2感染的转基因小鼠模型后，以及在细胞培养中，SARS-CoV-2能够在体内感染并扰乱视网膜色素上皮（RPE）。单独的慢病毒研究表明，SARS-CoV-2刺突蛋白介导病毒进入RPE细胞并在其中复制，而包膜蛋白和开放阅读框3a蛋白会诱导形态变化。感染SARS-CoV-2的主要变体损害了RPE屏障功能和吞噬能力。它还导致补体激活以及细胞因子和趋化因子的产生，引发炎症反应并扩散至整个RPE层。这种炎症特征与年龄相关性黄斑变性（AMD）发病时的炎症特征相似，AMD是人类失明的主要原因，由RPE病变最终导致光感受器细胞丢失引起。因此，我们的研究结果表明，SARS-CoV-2感染RPE后的急性后遗症可能对视力产生长期影响，这或许与在感染HIV的个体中发现的AMD发生率增加情况相当，但由于SARS-CoV-2感染的人数众多，其对公共卫生的影响更大。
