Abstract

A microscope image shows one of the lab-grown brain organoids that researchers infected with coronavirus to see how the virus took over cell machinery and deprived nearby neurons of oxygen. They also observes antibodies that help to prevent the virus from latching onto a particular receptor at work (white), suggesting antibodies can prevent brain infection

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 whether the virus can infect the brain, or what the consequences of CNS infection are. 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 the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

doi: https://doi.org/10.1101/2020.06.25.169946

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Eric Song1,#, Ce Zhang2,3,#, Benjamin Israelow1,4, Alice Lu-Culligan1 , Alba Vieites Prado5 , Sophie Skriabine5 , Peiwen Lu1 , Orr-El Weizman1 , Feimei Liu1,6, Yile Dai1 , Klara Szigeti-Buck3,6, Yuki Yasumoto3,7 , Guilin Wang8 , Christopher Castaldi8 , Jaime Heltke8 , Evelyn Ng8 , John Wheeler8 , Mia Madel Alfajaro1,9, Etienne Levavasseur5 , Benjamin Fontes10, Neal G. Ravindra11,12 , David Van Dijk11,12 , Shrikant Mane2,8 , Murat Gunel2,3,13 , Aaron Ring1 , Syed A. Jaffar Kazmi14, Kai Zhang14, Craig B Wilen1,9 , Tamas L. Horvath6,15,16 , Isabelle Plu5,17, Stephane Haik5,17,18,10, Jean-Leon Thomas5,19, Angeliki Louvi3,13, Shelli F. Farhadian4,19, Anita Huttner20, Danielle Seilhean5,17, Nicolas Renier5 , Kaya Bilguvar2,8,*, Akiko Iwasaki1,16,21,22,*

1 Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA 2 Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA 3 Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA 4 Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06510, USA 5 Sorbonne Université, INSERM U1127, CNRS UMR 7225, Paris Brain Institute – ICM, Paris, France 6 Department of Biomedical Engineering, Yale University, New Haven, CT 06510, USA 7 Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA 8 Yale Center for Genome Analysis, West Haven, CT 06510, USA 9 Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06510, USA. 10 Yale Environmental Health and Safety, Yale University, New Haven, CT 06510, USA 11 Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA 12 Department of Computer Science, Yale University, New Haven, CT 06510, USA 13 Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA 14 Department of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania 15 Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06510, USA 16 Department of Molecular, Cellular, and Developmental Biology, Yale School of Medicine, New Haven, CT 06510, USA 17 Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neuropathologie, Paris, France 18 Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Cellule nationale de référence des maladies de Creutzfeldt-Jakob, Paris, France 19 Department of Neurology, Yale School of Medicine, New Haven, CT 06510, USA 20 Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA 21 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA

Reprinted for educational purposes and social benefit, not for profit. 

Learn More:

  • Coronavirus kills off BRAIN cells as it hijacks some to make copies of itself and starves others of oxygen, study finds – Daily Mail
    • An international team of researchers studied coronavirus in lab grown brain ‘organoids’ and mouse brains
    • They found clear evidence that the virus can take over brain cell machinery to make copies of itself
    • Brain cells near the infected ones were oxygen-deprived and dying
    • Studies suggest that anywhere from 30 to 84 percent of COVID-19 patients develop neurological symptoms
    • The new new study, published online ahead of peer review found that antibodies taken from a COVID-19 patient prevented infection in the lab-grown mini-brains
    • Verifying reports of delusions and brain fogs, new research reveals just how coronavirus attacks and kills brain cells to churn out more copies of itself. Collaborating scientists around the globe have shown that the virus burglarizes brain cells, using their machinery to replicate, in a study posted online this week, which has not yet been peer-reviewed or published in a journal. And in the process, the infection seems to suck up the oxygen from other brain cells near the ones it has invaded, eventually killing them.
    • So far, coronavirus’s effects on the brain don’t seem to be what is killing COVID-19 patients, but researchers say that an unchecked infection in cerebral cells could be deadly.
    • Dr Akiko Iwasaki, a Yale University immunologist, and her team used human brain ‘organoids’ – tiny lab-grown brains made from human stem cells – and mice to study coronavirus’s invasion in real time. In the organoids, SARS-CoV-2 not only took over the machinery of brain cells it invaded, it shifted them into high gear. ‘The hypermetabolic state is unique to the SARS-CoV-2 infected cells and highlights the ability of SARS-CoV-2 to hijack the host neuron machinery to replicate,’ the study authors wrote. While infected brain cells were busy cranking out more copies of the virus, it seemed to poison the environment around it.
    • Nearby cells go into break down mode – called catabolic metabolism – according to the new study. As suspected by researchers who have conducted previous studies on COVID-19 and the brain, they found signs of oxygen deprivation in and around those neighboring cells. The combined effects sent these cells into their their death spiral, as evidenced by ‘upregulation of cell death’ processes, in scientific terms. Brain cells, called neurons, communicate with one another through electrical signals.
    • In a healthy brain, these impulses move seamlessly and quickly through a vast network of neurons, like massive, intricately connected information superhighway. But, like potholes on a road, patches of dead cells interrupt the flow of that information. As a result, people with traumatic brain injuries or in the early stages of Alzheimer’s may have ‘brain fog,’ as information tumbles over these dead zones in the brain. Viral infections don’t usually stick around long enough to cause the devastation that Alzheimer’s does, but if a virus is killing off brain cells, as SARS-CoV-2 seems to, this too can cloud cognition or cause delirium. And studies suggest it has, for a significant portion of patients with COVID-19. Research published in June in the New England Journal of Medicine found that as many as 84 percent of COVID-19 patients developed neurological symptoms, such s headache, delirium, trouble with memory or attention, and burning or prickling sensation.
    • Another study found that about a third of patients had neurological symptoms. Patients who died of coronavirus were found to have signs of a dangerous form of brain swelling in autopsy studies. Some of their brain cells had died off too. Now that it’s clear that coronavirus can attack the brain, scientists need to work out how it gets there, and what to do about it, both of which remain unclear. However, in one encouraging development, the authors of the new study, published Wednesday, found antibodies against the infection in the cerebrospinal fluid of a COVID-19 patient. When they exposed a brain organoid to these antibodies, the immune proteins successfully blocked the lab-grown brains from getting infected. That’s an encouraging sign that a vaccine or antibody treatments being developed – if each proves safe in trials – could protect the brain from coronavirus.