randombio.com | science
Saturday, September 12, 2020

Sars-CoV-2 messes with your head

Some researchers are finding evidence that deaths from COVID-19 may actually be due to brain infection.

T his week I got an email from a company offering me a free face mask if we ask them for a quote to make a custom antibody. It's making me seriously wonder that maybe this SARS-CoV-2 really does screw up people's brain.

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I haven't been following the controversy over whether masks actually work: does saying they work get you censored on Twitter, or does saying they don't work get you censored? I don't know. Maybe it changes from day to day. The real question is: has anyone ever actually changed their face mask? I've been wearing the same blue paper mask for the past month. Some of my fellow faculty members think it's all a bit silly, but they dutifully put them on when someone enters the room because their employer says they must. Maybe masks are like race: no matter what you say on the subject, you get criticized.

A custom polyclonal antibody costs a few thousand dollars. A custom monoclonal costs about twenty thousand dollars. Facemasks are $22.95 for a pack of fifty. If you're willing to take a chance, you can get a box of fifty really cheap Made in China masks for $9.99. But reports are trickling in that Sars-CoV-2, aka the Wuhan coronavirus, really does mess with your head, and not in a funny way, and not just in a few percentage of patients.

Neurovirulence of SARS-CoV-2

It used to be thought that neurodegeneration caused by SARS-CoV-2 was either due to its ability to cause blood coagulation (evidenced by elevated levels of D-dimer) or to its ability to release massive amounts of cytokines, which can cross the blood-brain barrier and trigger neuroinflammation. But a new paper from the University of Nebraska [1] says that betacoronaviruses get into the brain via the bloodstream or by infecting a peripheral nerve and traveling to the brain through the nerve. SARS-CoV-2 is therefore both neurotropic and neurovirulent, which means it directly infects the brain cells, including neurons and microglia, and causes an inflammatory cascade that results in cell damage, seizures, delirium, and stroke. This is made possible by the presence of ACE2, the virus's receptor, on neurons and endothelial cells.

Once in the brain, the virus particles specifically enter the brainstem, where they can cause cardiac and respiratory dysfunction. The particles encounter little resistance from the brain's innate immune system. Cytolytic T cells are a bad thing to have in the brain, as they would cause neuro­degen­er­ation, so there are very few of them in the brain. Instead the brain relies on its microglia and the complement system, which target pre-defined molecular motifs and can destroy cells that display signs of injury.

This is not just happening in a small subset of patients: a retrospective study found that 36.4% of surviving patients out of 214 confirmed cases had neurological problems, including delirium, cognitive impairment, loss of smell and taste, and acute cerebrovascular disease (stroke).[2]

Patients with multiple sclerosis are at even higher risk of CoV neuroinvasion, possibly because they're treated with corticosteroids, which puts them in an immunocompromised state. This is why the recent idea of giving dexamethasone is a risky proposition. The authors recommend measuring virus in the CSF (cerebrospinal fluid, i.e. a spinal tap) to test for CNS infection.

And you thought the idea of sticking a giant foot-long Q-tip up your nose was scary.

Neuroinvasion of SARS-CoV-2

Another paper from Yale School of Medicine, currently a non-peer-reviewed preprint at bioRxiv,[3] says that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality, at least in mice. I'll say that again: if this is true for humans, it implies that the patients who died may have died, not from respiratory infection, but because the virus infected their brain.

The way this probably happens is again via the brainstem, which controls breathing and heart function. But in the autopsy samples they also found multiple microscopic ischemic infarcts in the subcortical white matter, indicating that the virus is starving the brain cells for oxygen.

This study was done exclusively in mice, human brain organoids, and post-mortem tissues from COVID-19 patients, but the results are credible. Organoids are small clumps of human brain cells that replicate the environment of the brain. The organoids were rapidly infected by virus particles and underwent extensive neuronal cell death, even—or especially—if no virus was in them. This means infected cells can somehow kill nearby neurons.

It turned out that what was happening was that the SARS-CoV-2-infected neurons were in a hypermetabolic state as the virus sped up the cells trying to replicate. In so doing, the infected cells depleted the oxygen, causing nearby neurons to die from hypoxia.

ACE2 was required for the virus to infect the cells. Contrary to the myth that ACE2 is not expressed in neurons, they found that the level of ACE2 messenger RNA (which is usually taken to mean low levels of protein expression) does not accurately reflect the amount of ACE2 protein on the cells.


The COVID-19 pandemic is practically over. The conclusion laymen can draw from this is to seriously consider getting a vaccination once it is demonstrated to be safe and effective. A lung can repair itself if it's not too badly damaged. A brain cannot.

The other question it raises is: was the total batshit craziness that swept the country after the pandemic really caused by fear and panic, or could the virus have contributed to it? This is looking more and more like the epidemic of schizophrenia that happened after the 1918 Spanish flu.

1. Acharya A, Kevadiya BD, Gendelman HE, Byareddy SN (2020). SARS-CoV-2 Infection Leads to Neurological Dysfunction. J Neuroimmune Pharmacol May 23 2020 https://doi.org/10.1007/s11481-020-09924-9

2. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2020. 1127

3. Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman O, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Fontes B, Ravindra ND, Van Dijk D, Mane S, Gunel M, Ring A, Kazmi SAJ, Zhang K, Wilen CB, Horvath TL, Plu I, Haik S, Thomas JL, Louvi A, Farhadian SF, Huttner A, Seilhean D, Renier N, Bilguvar K, Iwasaki A (2020). Neuroinvasion of SARS-CoV-2 in human and mouse brain. bioRxiv preprint doi: https://doi.org/10.1101/2020.06.25.169946.

sep 12 2020, 5:10 pm

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