期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：30
DOI：10.1073/pnas.2122236119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Neurological and neuropsychiatric symptoms occur in as many as one-third of patients with or recovering from COVID-19. To address severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neural tropism, we evaluated the vulnerability of primary developing and adult cortical tissue and stem-cell-derived cortical organoids to SARS-CoV-2 infection. We observe robust infection and viral replication in human cortical astrocytes; they become reactive, have increased growth factor signaling, and activate cellular stress. Despite infection in astroglial cells, there is minimal infection of other neural cell types, including neurons. Surprisingly, we discover that astrocyte infection is unlikely to be mediated by the predominant coronavirus receptor, ACE2, and instead observe alternative glycoproteins, CD147 and DPP4, expressed on astrocytes; they are necessary and sufficient for SARS-CoV-2 infection.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. Neurological symptoms, which range in severity, accompany as many as one-third of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived cortical organoids as well as primary human cortical tissue, both from developmental and adult stages. We find significant and predominant infection in cortical astrocytes in both primary tissue and organoid cultures, with minimal infection of other cortical populations. Infected and bystander astrocytes have a corresponding increase in inflammatory gene expression, reactivity characteristics, increased cytokine and growth factor signaling, and cellular stress. Although human cortical cells, particularly astrocytes, have no observable ACE2 expression, we find high levels of coronavirus coreceptors in infected astrocytes, including CD147 and DPP4. Decreasing coreceptor abundance and activity reduces overall infection rate, and increasing expression is sufficient to promote infection. Thus, we find tropism of SARS-CoV-2 for human astrocytes resulting in inflammatory gliosis-type injury that is dependent on coronavirus coreceptors.
