Latest Research Suggests COVID-19 Affects the Brain, Raises Even More Questions

By Sheeva Azma and Nidhi Parekh

This post by Sheeva Azma of Fancy Comma, LLC and Nidhi Parekh of The Shared Microscope is a larger part of a series on COVID-19. Sheeva Azma is a neuroscientist and science writer with a B.S. in Brain & Cognitive Science from MIT and an M.S. in Neuroscience from Georgetown University. Nidhi Parekh is an occupational disease paralegal at a top insurance firm in the UK. She has a BSc Honors in Biomedicine from the University of East Anglia (Norwich, UK) and a Graduate Diploma in Law from BPP University (London, UK). Check out Sheeva and Nidhi’s other posts on COVID-19, including how the most promising COVID-19 vaccines work, here.

Recent research conducted by Yale University reveals the harmful effects of the novel coronavirus in the brain. However, these new revelations raise more questions than they answer.  Read on to learn more about the effects of COVID-19 on the brain, as well as what remains unclear about the effects of the novel coronavirus pandemic.

For the past several months, we’ve all been taking the necessary precautions to reduce the spread of COVID-19.  Social distancing, masking, and hand washing are now part of our daily lives.  Such is life in a pandemic for which there is no cure.

Most people, by now, know that COVID-19 is a respiratory disease.  When we do things like cough, sneeze, or even talk, our lungs release droplets that can spread the disease through the air.  Another emerging fact? COVID-19 affects different organ systems besides the lungs — including the heart, blood vessels, and, as new research shows, even the brain.

Recent research shows that COVID-19 not only affects the lungs, heart, and blood vessels, but also the brain. @TheSharedScope #COVID19 #neuroscience

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So how does this all happen?  That’s what we will talk about in this post.  While it’s difficult to understand a virus that has been known for only a few months, scientists have made strides in understanding the novel coronavirus.

COVID-19 Patients Report Many Neurological Symptoms

COVID-19 patients can suffer from a variety of neurological symptoms.  Less severe COVID-19 neurological symptoms can include headaches, brain fog, memory problems, and loss of sense of smell and taste, while the more severe issues can include brain inflammation, hemorrhage, seizures, stroke, Guillain-Barré syndrome, peripheral nerve damage, and other nervous system disorders which remain unclear (Paterson, et al, 2020).  

Dr. Elissa Fory, a neurologist, told the New York Times about one case “consistent with viral inflammation of the brain … this may indicate that the virus can invade the brain directly in rare circumstances.”  The novel coronavirus has also been found in the cerebrospinal fluid of a patient in Los Angeles (Huang, et al., 2020).  It’s clear that COVID-19 impacts the brain, and scientists are beginning to find out why.

Many Roads to Brain Problems in COVID-19

In her article in the New York Times, Melinda Wenner Moyer talks about COVID-19’s potentially damaging effects on the brain:  

Direct Infection of Brain Cells

As Moyer writes, the novel coronavirus can either “directly infect neural cells,” or indirectly via “widespread inflammation caused by the body’s immune response.”

Indirect Infection of Brain Cells (Too Much Inflammation)

Brain inflammation is the basis of many neurodegenerative disorders and can lead to major problems.  In COVID-19, the body’s immune system reacts in what is called a “cytokine storm.”  During this immune overreaction, the cytokines can attack and infiltrate the blood-brain barrier.  Without the blood-brain barrier intact, viruses and immune cells can enter the brain, causing major problems.

Problems with Blood Clotting

According to Robert Stevens, MD, of Johns Hopkins Medicine,  an additional mechanism by which COVID-19 affects the brain is via problems with blood clotting.  COVID-19 affects blood clotting and makes it more likely to occur in some patients, which can form deep inside the body, including the brain, where they could cause a stroke.

SARS-CoV-2, the virus causing COVID-19, can infect brain cells directly or indirectly, or cause problems with blood clotting that can lead to strokes and other neurological problems. @TheSharedScope

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What Is the Mechanism for COVID-19’s Effects on the Brain?

Prof. Akiko Iwasaki is an immunology researcher at Yale University, who can be found @VirusesImmunity on Twitter.  She recently led a study (Song, et al., 2020) looking at brain infection in COVID-19.  Her study looked at COVID-19 infection in the human brain from someone who succumbed to COVID-19, as well as in a mouse model of the disease, and small groups of brain cells grown in a lab.  She found that the novel coronavirus reduces the number of connections between neurons just days after an infection.  Rather than destroying brain cells, the novel coronavirus prevents adjacent cells from obtaining oxygen, which causes the surrounding brain cells to die off. 

A recent study by @VirusesImmunity shows that the novel coronavirus replicates in brain cells, depriving surrounding brain cells of oxygen, reducing brain cell connections, and causing cell death. @TheSharedScope

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One thing that is known is that a receptor called ACE2 receptor is the entry point for the virus that causes COVID-19.  This receptor is found on cells all over the body and, as Prof. Iwasaki’s study shows, in the brain, too — a place where researchers previously did not think it existed.

In the next section, we’ll talk about the ACE2 receptor and how it works to cause a COVID-19 infection in the body — and, as Prof. Iwasaki’s research indicates, in the brain as well.

How Does a COVID-19 Infection Occur? ACE2 Is the Key (Literally)

Before we get into the specifics of how the ACE2 receptor is involved in neurological problems in COVID-19, let’s first quickly discuss how a COVID-19 infection takes hold.

COVID-19 is caused by the novel coronavirus, SARS-CoV-2.  The virus interacts with a receptor in our bodies called Angiotensin-converting enzyme 2 (ACE2) receptor. 

The ACE2 receptor allows SARS-CoV-2 to get into our cells and cause a COVID-19 infection (MacLachlan, 2020).  In normal circumstances, angiotensin binds to ACE2 receptors on the surface of the cell to modulate downstream behaviours within the cell. The SARS-CoV-2 virus competitively binds to ACE2 receptors. This means that in high concentrations of SARS-CoV-2, the chances of the virus binding to the ACE2 receptor is higher than the chances of angiotensin binding to it. 

The novel coronavirus binds to the ACE2 receptor, outcompeting other molecules. With lots of SARS-CoV-2 in the body, the virus is more likely to bind to ACE2, so COVID-19 infection could be much more severe. @TheSharedScope

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What is the ACE2 receptor?  

It is a receptor that is found on the cell membranes of organs including the lungs, arteries, heart, kidneys, and intestines.  Besides serving as a way for SARS-CoV-2 to enter our cells, the ACE2 receptor also lowers blood pressure by breaking down a chemical called angiotensin II that increases blood pressure.  Because of its role in the cardiopulmonary and circulatory systems, the ACE2 receptor is a promising drug target for cardiovascular disease.  The ACE2 receptor itself is essential for good heart health, as loss of ACE2 can result in “age-dependent cardiomyopathy … and enhances the [heart’s] susceptibility to mechanical stress”  (Oudit et al., 2009).

Here are three things you need to know about how ACE2 contributes to a COVID-19 infection:

1. SARS-CoV-2 uses its spike proteins to get into a human cell.  The SARS-CoV-2 virus, which is the virus that causes a COVID-19 infection, uses its spike proteins to leverage its attack on the body.  You can read more about spike proteins at our post at Bolded Science.  As we write:
   

“SARS-CoV-2 causes infection in people via spike proteins found on its surface.  The infection that the virus causes is called COVID-19. The virus’s spike proteins help the virus interact with cells in our lungs (as well as other organs and even, perhaps, the lining of our blood vessels), to eventually enter and infect these cells.  Once the SARS-CoV-2 virus is in our cells, thanks to the spike proteins, the virus can multiply and cause COVID-19 infection.  Since spike proteins are vital to causing COVID-19 infection, the majority of vaccines in development are aimed at the spike proteins as a way to prevent a COVID-19 infection.”

Source: Bolded Science

2. To enter the human cell, the SARS-CoV-2 spike protein interacts with a cell receptor called the ACE2 receptor.  The novel coronavirus’s spike protein unlocks the human cell membrane.  The virus does this via interacting with ACE2 receptors on the surface of our cells.  In other words, the ACE2 receptor is SARS-CoV-2’s ticket into the cell.
   
3. Once the novel coronavirus is in the cell, it can use the cell’s machinery to make copies of itself.  Once the virus has made enough copies of itself, the cell will burst open and die, releasing more SARS-CoV-2 which will repeat this process.  This process leads to the development of COVID-19, as soon, the virus is proliferating all over the body.

The novel coronavirus, SARS-CoV-2, uses a cell membrane receptor called ACE2 to get into human cells to create copies of itself and cause a COVID-19 infection.  ACE2 receptors are found all over the body — including lungs, heart, kidneys, gastrointestinal system, and even the brain — but the process is depicted here in a lung epithelial cell.  Source: Nidhi Parekh of The Shared Microscope on Instagram (click here for the original post).

The novel coronavirus, SARS-CoV-2, uses a cell membrane receptor called ACE2 to get into human cells to create copies of itself and cause a COVID-19 infection. @TheSharedScope

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The ACE2 System’s Role in the Brain

By now, as we’ve discussed, scientists know that the ACE2 system plays a role in many pathophysiological states in the heart, lungs, and elsewhere, and that they play a role in human coronaviruses like the virus that caused SARS in 2003.  As Xia and Lazartigues (2008) write, “Decreases in ACE2 expression and activity have been reported in models of hypertension, heart failure, atherosclerosis, diabetic nephropathy, and others.”  Oudit et al., 2009, note that ACE2 receptor is dysregulated in acute lung injury and in response to pulmonary infection with the original SARS virus, SARS-CoV.

ACE2 receptors, which were previously thought not to exist in the brain, are rich in certain areas of the brain and can serve as an entry point for the SARS-CoV-2 virus that causes COVID-19. @TheSharedScope

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The brain also has ACE2 receptors “widespread throughout the brain” that functions both to regulate cardiovascular function as well as other brain functions such as motor cortex and movement and raphe nuclei which are serotonin neurons found in the brainstem (Xia and Lazartigues, 2008).

Interestingly, as Xia and Lazartigues report in 2008 regarding the original SARS virus, that “SARS‐CoV [the virus causing SARS] has been detected in brains of infected patients, almost exclusively in neurons, suggesting the distribution of ACE2 [receptors in] the CNS.”

Recent studies fast-tracked in the COVID-19 pandemic have largely not been subject to peer review, but may offer some insights into where these receptors could be residing in the brain.  Chen and colleagues (2020) looked at data on ACE2 receptor expression in the brain via combining genetics databases for both humans and rodents, and found that ACE2 was expressed very highly in “some important brain areas” such as:

• Substantia nigra, an area of the brain which contains dopamine neurons involved in both movement and reward
• The brain’s ventricles, which contain a compound called cerebrospinal fluid that protect the brain from injury and deliver important nutrients to various regions of the brain

ACE2 receptors were also found in the following human brain areas:

• Middle temporal gyrus, which deals with language and language-related memory (Onitsuka, et al., 2004)
• Posterior cingulate cortex, a region of the brain which is poorly understood but, though typically protected from ischemic damage, is implicated in aging as well as many neurodegenerative and neuropsychiatric diseases (Leech and Sharp, 2014)
• Piriform cortex, which is the area of the brain which processes olfactory (smell) information and smell-related memories (Vismer, 2015).
• ACE2-expressing cells were also found in minute levels in the hippocampus, an area of the brain that deals with memory and cognition.

ACE2 receptors were found in both brain cells as well as glia (the brain’s non-neuronal cells which perform important scaffolding and immune functions) in this study.  For the neuroscience-minded, a figure from this paper which discusses all of the human brain regions with ACE2 receptors can be found here as Figure 2 of this paper.

Unanswered Questions in COVID-19 and the Brain

Over the past few months, researchers have made great progress in understanding the mysteries of SARS-CoV-2, and the COVID-19 it causes, and how it can be so devastating.  Yet, it seems like as more questions are answered, even more questions are raised.

A few outstanding questions regarding COVID-19 and the brain are:

• How does COVID-19 get into the brain?
  
• Are there certain places the novel coronavirus can be found in the brain more than others?  Would these areas (for example, areas discussed above rich with ACE2) be more susceptible to brain damage?
  
• What types of patterns of brain problems would you see in a low-risk versus high-risk person?  Would they be the same?  Different?
  
• Are these brain issues at all reversible?
  
• Does this brain damage occur for asymptomatic patients?

Serious Neurological Effects of COVID-19 Highlight Need for a Vaccine or Cure

These neural consequences put the AstraZeneca trials in a different perspective.  In early September 2020, AstraZeneca’s Phase 3 trials for their COVID-19 vaccine were paused due to a participant being under investigation regarding a rare, serious condition called transverse myelitis, characterized by inflammation of the spinal cord.  As STAT News reports, researchers also temporarily halted the clinical trial in July 2020, after a participant was diagnosed with Multiple Sclerosis, an autoimmune nervous system condition, which was found to be unrelated to the vaccine trials.  According to AstraZeneca, these trials have now resumed.

Recall from our interview with a clinical trials participant, that participants in the Oxford/Astrazeneca trials either receive the COVID-19 vaccine or a control vaccine, a meningitis vaccine.  Remember also, from our post on the Oxford/Astrazeneca vaccine, that the vaccine only contains a part of the SARS-CoV-2 virus’s structure, so it cannot cause a COVID-19 infection.

Especially given what scientists have recently learned about the harmful effects of COVID-19 on the brain, a vaccine for the novel coronavirus is needed. @TheSharedScope

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In a perfect world, a clinical trial would have not have any ill effects; yet, overall, we can say the low incidence of adverse effects suggests that the vaccine continues to be promising.  Especially given what is now known about the effect of COVID-19 on the brain, a vaccine that has been, so far, proven to be safe and effective in clinical trials could help mitigate the mortality from the virus that has been gripping the world since late 2019.

Conclusions

The recent news about neurological symptoms of COVID-19 should give people around the world great pause.  We must all exercise the utmost caution so that we do not contract a disease with no cure with potentially severe neurological consequences.  Scientists and doctors are gaining ground on COVID-19 and how it works, but many questions remain unresolved.

This post is a collaboration with The Shared Microscope. Check out their Twitter, hop over to their Facebook, or visit their Instagram for informative, effective illustrations of concepts in biology. Check out Fancy Comma, LLC and The Shared Microscope‘s other posts on COVID-19, including detailed explainers on how the frontrunner COVID-19 vaccines work, here.