Neuroinvasion of SARS-CoV-2 in human and mouse brain

• Published in: The Journal of experimental medicine Vol. 218; no. 3
• Main Authors: Song, Eric, Zhang, Ce, Israelow, Benjamin, Lu-Culligan, Alice, Prado, Alba Vieites, Skriabine, Sophie, Lu, Peiwen, Weizman, Orr-El, Liu, Feimei, Dai, Yile, Szigeti-Buck, Klara, Yasumoto, Yuki, Wang, Guilin, Castaldi, Christopher, Heltke, Jaime, Ng, Evelyn, Wheeler, John, Alfajaro, Mia Madel, Levavasseur, Etienne, Fontes, Benjamin, Ravindra, Neal G., Van Dijk, David, Mane, Shrikant, Gunel, Murat, Ring, Aaron, Kazmi, Syed A. Jaffar, Zhang, Kai, Wilen, Craig B., Horvath, Tamas L., Plu, Isabelle, Haik, Stephane, Thomas, Jean-Leon, Louvi, Angeliki, Farhadian, Shelli F., Huttner, Anita, Seilhean, Danielle, Renier, Nicolas, Bilguvar, Kaya, Iwasaki, Akiko
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01.03.2021
• Subjects: Angiotensin-Converting Enzyme 2 - antagonists & inhibitors; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Antibodies, Blocking - chemistry; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Cerebral Cortex - virology; COVID-19 - metabolism; COVID-19 - pathology; Disease Models, Animal; Female; Human health and pathology; Humans; Infectious Disease and Host Defense; Life Sciences; Male; Mice; Middle Aged; Neurons - metabolism; Neurons - pathology; Neurons - virology; Organoids - metabolism; Organoids - pathology; Organoids - virology; SARS-CoV-2 - metabolism
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20202135

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.