Productive infection of the retinal pigment epithelium by SARS-CoV-2: Initial effects and consideration of long-term consequences

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.