Neurological symptoms apparently not a result of SARS-CoV-2 infection of the brain

[SWAlexander]

Scientists still are not sure how neurological symptoms arise in COVID-19. Is it because SARS-CoV-2 infects the brain? Or are these symptoms the result of inflammation in the rest of the body? A study by Charité – Universitätsmedizin Berlin has now produced evidence to support the latter theory. It was published today in the journal Nature Neuroscience.*

Headaches, memory problems, and fatigue are just some of the neurological impacts that arise during coronavirus infection and can last well beyond the acute period. Even early on in the pandemic, researchers surmised that direct infection of the brain could be the cause. “We took that as our hypothesis at the start, too. But so far, there has been no clear evidence that the coronavirus can persist in the brain, let alone proliferate,” explains Dr. Helena Radbruch, head of the Chronic Neuroinflammation working group at the Department of Neuropathology at Charité. “For that, we would have needed to find evidence of intact virus particles in the brain, for example. Instead, the indications that the coronavirus could infect the brain come from indirect testing methods, so they aren’t entirely conclusive.”

According to a second hypothesis, the neurological symptoms would instead be a kind of side effect of the strong immune response the body deploys to defend against the virus. Past studies had produced indications that this might be the case. The current Charité study now bolsters this theory with detailed molecular biology and anatomical results from autopsies.

No signs of direct infection of the brain

For the study, the team of researchers analyzed various areas of the brain in 21 people who died in hospital settings, typically in an ICU, due to severe coronavirus infection. For comparison, the researchers studied nine patients who died of other causes after treatment in intensive care. First, they looked to see whether the tissue showed any visible changes and hunted for any indication of coronavirus. Then they conducted a detailed analysis of genes and proteins to identify the specific processes that had taken place inside individual cells.

Like other teams of researchers before them, the Charité scientists found coronavirus genetic material in the brain in some cases. “But we didn’t find neurons infected with SARS-CoV-2,” Radbruch notes. “We assume that immune cells absorbed the virus in the body and then traveled to the brain. They’re still carrying the virus, but it doesn’t infect cells of the brain. So coronavirus has invaded other cells in the body, but not the brain itself.”

Brain reacts to inflammation in the body

Still, the researchers did note striking changes in molecular processes in some cells of the brain in those infected with COVID-19: For example, the cells ramped up the interferon signaling pathway, which is typically activated in the course of a viral infection. “Some neurons evidently react to the inflammation in the rest of the body,” says Prof. Christian Conrad, head of the Intelligent Imaging working group at the Berlin Institute of Health at Charité (BIH) and one of the principal investigators in the study, along with Radbruch. “This molecular reaction could be a good explanation for the neurological symptoms we see in COVID-19 patients. For example, neurotransmitters emitted by these cells in the brainstem could cause fatigue. That’s because the brainstem is home to groups of cells that control drive, motivation, and mood.”

continue reading: https://www.charite.de/en/service/press_reports/artikel/detail/how_covid_19_affects_the_brain/

 

[Wishful]

That supports my beliefs about ME: that an immune response elsewhere affects how the brain functions. The lack of highly elevated cytokines means that it could be that those brain cells are overly sensitive to normal levels of cytokines, or remain in that abnormal state even without cytokines.

I hope this shifts research funding from antivirals to how the brain responds to immune activation elsewhere in the body.

 

[SWAlexander]

abnormal state even without cytokines.

...and activating apoptosis. The question remains if and how the death cells are removed.
When cells undergo apoptosis, they undergo a series of changes that signal their need for removal.

Normally, and if the system functions well, phagocytes, such as macrophages and dendritic cells, recognize these signals through their receptors. Once recognized, the phagocytes engulf the apoptotic cells, encapsulating them in a phagosome. The phagosome then fuses with lysosomes, forming a phagolysosome where the engulfed cell is degraded by lysosomal enzymes.

This process is crucial for maintaining tissue homeostasis and preventing the release of potentially harmful intracellular contents into the surrounding tissue, which could trigger inflammation or an immune response (cytokines).

 

[Wishful]

The question remains if and how the death cells are removed.

Hmmm, now I'm imagining zombie brain cells wandering around my brain. "Brainsss!"

 

[SWAlexander]

cells wandering around my brain

Don't forget the CSF (spine).

 

[godlovesatrier]

The thing is when I had acute covid I didn't feel that bad. My worst symptoms so far are only kicking in about 4 to 8 weeks post.

This last week has been really bad, I've deteriorated a lot. Sound sensitivity and moderate brainfog (enough to make tv watching difficult) with some mild pots possibly not sure has crept in. That aligns with upper body fatigue and a painful neck/shoulders due to head feeling too heavy for head - typical pots really.

So whilst it's great they did the study you do wonder what methods they used to look at the brain tissue, what sort of staining they did. And with LC patients, especially the majority I guess now who had mild infections (mine was clinically mild but for me it was severe), I wonder what there brains look like.

 

[SWAlexander]

That aligns with upper body fatigue and a painful neck/shoulders due to head feeling too heavy for head - typical pots really.

I hear you. I felt this way for nearly 1 year. the skeletal muscles are too weak to hold anything in place.

How a brain looks after covid is scary.
See for yourself:

https://twitter.com/i/web/status/1756117668971880777

 

[godlovesatrier]

Is this from severe patients or mild patients? Because there's a mahoosive difference in terms of pathology between the two. Even if they both get long covid. One might get everything back cognitively, the other may have issues the rest of their life - or die in the proceeding years.

 

[Hip]

Like other teams of researchers before them, the Charité scientists found coronavirus genetic material in the brain in some cases. “But we didn’t find neurons infected with SARS-CoV-2,” Radbruch notes. “We assume that immune cells absorbed the virus in the body and then traveled to the brain. They’re still carrying the virus, but it doesn’t infect cells of the brain. So coronavirus has invaded other cells in the body, but not the brain itself.”

They did not find SARS-CoV-2 in the neurons; but there are other cells in the brain, such as astrocytes and the cells of the blood vessels passing through the brain.

In one enterovirus ME/CFS brain autopsy study, they found enterovirus in the astrocytes and in the blood vessel cells.

 

[SWAlexander]

astrocytes

According to Histology, Astrocytes - StatPearls - NCBI Bookshelf https://www.ncbi.nlm.nih.gov/books/NBK545142/
Astrocytes are a subtype of glial cells that make up the majority of cells in the human central nervous system (CNS). They perform metabolic, structural, homeostatic, and neuroprotective tasks such as clearing excess neurotransmitters, stabilizing and regulating the blood-brain barrier, and promoting synapse formation.

On the other side, what is an astrocyte and its function?

Astrocytes not only regulate blood flow, but also transfer mitochondria to neurons, and supply the building blocks of neurotransmitters, which fuel neuronal metabolism. In addition, astrocytes can phagocytose synapses, alter neurotrophin secretion, and clear debris.

Now, I question how anything can breach the blood-brain barrier (BBB) if astrocytes are on guard.

I've been questioning academia for a while (which is somewhat detached from science) about its tendency to announce inconclusive results. It should instead allow true science to find answers. The BBB must have entry points; otherwise, how could conditions like dementia or Alzheimer's take hold of the brain?

 

[Hip]

Now, I question how anything can breach the blood-brain barrier (BBB) if astrocytes are on guard.

Dr Chia has pointed out that enteroviruses can travel from the gut into the brain via the vagus nerve. Enterovirus takes just 3 days to travel along this nerve and into the brain using retrograde axonal transport.

Other viruses such as herpes simplex can enter the brain via the olfactory nerves.

One COVID study I saw found that the vagus nerve of deceased COVID patients (not long COVID patients) was infected with SARS-CoV-2. This finding provides support for the vagus nerve infection hypothesis of ME/CFS.

 

[SWAlexander]

vagus nerve of deceased COVID patients (not long COVID patients) was infected with SARS-CoV-2

I read this paper too. At the same time "Charité - Universitätsmedizin Berlin" comes out with "Scientists still are not sure how neurological symptoms arise in COVID-19. Is it because SARS-CoV-2 infects the brain? Or are these symptoms the result of inflammation in the rest of the body?" https://www.eurekalert.org/news-releases/1034659

It all depends on how deep each study goes.

From my research archive: https://swaresearch.blogspot.com/2024/02/the-lymphatic-system-interacting-with.html
The lymphatic system plays a crucial role in the immune response by transporting lymph, a fluid containing white blood cells and lymphocytes, throughout the body. This system helps in removing toxins, waste, and unwanted materials from the body, including the identification and fighting of infections caused by bacteria, viruses, and other pathogens.
In the context of the brain, recent research has unveiled the presence of a lymphatic system within the central nervous system (CNS), challenging the long-standing belief that the brain was "immune privileged" due to the blood-brain barrier. This discovery has shed light on the mechanisms through which the immune system interacts with the brain.
The lymphatic vessels in the CNS, specifically those found in the meninges (the membranes covering the brain and spinal cord), facilitate the drainage of cerebrospinal fluid (CSF) into the deep cervical lymph nodes. This process allows for the removal of waste products from the CNS and also plays a role in the immune surveillance of the brain. It provides a pathway for immune cells to enter and exit the CNS, thus participating in the immune response to infections and diseases within the brain.
Therefore, the lymphatic system is involved in transporting immune cells and possibly pathogens, including viruses and bacteria, to and from the brain, albeit in a highly regulated manner to prevent unnecessary immune responses that could damage the CNS. This system helps maintain the delicate balance between protecting the brain from pathogens and preventing harmful inflammation.

 

[SWAlexander]

Additional information about brain infection and astrocytes.
"They found monkeypox virus infiltrated the astrocytes — a type of cell responsible for normal brain function — triggering an extreme immune response." https://www.ualberta.ca/folio/2024/...nkeypox-virus-may-infiltrate-brain-cells.html

 

[pattismith]

...and activating apoptosis. The question remains if and how the death cells are removed.
When cells undergo apoptosis, they undergo a series of changes that signal their need for removal.

Normally, and if the system functions well, phagocytes, such as macrophages and dendritic cells, recognize these signals through their receptors. Once recognized, the phagocytes engulf the apoptotic cells, encapsulating them in a phagosome. The phagosome then fuses with lysosomes, forming a phagolysosome where the engulfed cell is degraded by lysosomal enzymes.

This process is crucial for maintaining tissue homeostasis and preventing the release of potentially harmful intracellular contents into the surrounding tissue, which could trigger inflammation or an immune response (cytokines).

It has been demonstrated that MBL plays a role in clearing apoptic cells, and that MBL deficiency is linked to a defect of apoptic cell clearance... Maybe one reason why MBL deficient people are more sensitive to ME/CFS?

https://www.uniprot.org/citations/15749852

Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype.​

 

[SWAlexander]

MBL deficient people are more sensitive to ME/CFS

I wish I knew. I have not seen any papers that have made a connection with ME/CFS. Another question remains: how many people with ME/CFS are tested for MBL or diagnosed with a deficiency? Examples include lupus, rheumatoid arthritis (RA), psoriasis, etc.

There is extensive literature available on MBL.

Mannose-binding lectin (MBL) deficiency:
https://www.immunodeficiencyuk.org/mannose-binding-lectin-mbl-deficiency-2/​

Inherited mannose-binding lectin deficiency as evidenced by genetic and immunologic analyses: association with severe recurrent infections: https://pubmed.ncbi.nlm.nih.gov/14582818/ ​

​

 

[SWAlexander]

defect of apoptic cell clearance

Why death cells linger in ME/CFS is not established yet.
At least Danielle Beckman found evidence in COVID infection:
"I strongly believe all these neuroinflammatory responses contribute to "brain fog" and #LongCovid.
These processes can start very fast but can be very slow for the brain's immune system to clean up the mess after it."

https://twitter.com/i/web/status/1759409769629335892

 

[SWAlexander]

Gaps allow substances to move in and out of the brain​

Excerpt:
When examining different cell types in the layers of the mouse brain, the team noted that arachnoid barrier cells were found around blood vessels called bridging veins. These veins punch through the arachnoid barrier. The spaces around them were thought to be sealed tightly, like caulking around a pipe. However, the researchers found that the arachnoid barrier cells formed leaky cuffs around the bridging veins. They called these tiny openings arachnoid cuff exit (ACE) points.

Using high-powered microscopy and fluorescent tracers, the team observed molecules crossing from the inner layers of the meninges into the dura mater through these ACE points in live mice. Once these molecules reached the dura mater, they had direct access to the regions where waste drains out of the brain.

Correspondingly, the team found that molecules could also flow the other way across ACE points, from the dura mater across the arachnoid barrier and into the brain. In a mouse model of brain inflammation, the team observed changes in the ACE points that facilitated a harmful excess of immune cells to flow across the meninges.
https://www.nih.gov/news-events/nih-research-matters/gaps-allow-substances-move-out-brain

 

[Apollonia]

The thing is when I had acute covid I didn't feel that bad. My worst symptoms so far are only kicking in about 4 to 8 weeks post.

This last week has been really bad, I've deteriorated a lot. Sound sensitivity and moderate brainfog (enough to make tv watching difficult) with some mild pots possibly not sure has crept in. That aligns with upper body fatigue and a painful neck/shoulders due to head feeling too heavy for head - typical pots really.

So whilst it's great they did the study you do wonder what methods they used to look at the brain tissue, what sort of staining they did. And with LC patients, especially the majority I guess now who had mild infections (mine was clinically mild but for me it was severe), I wonder what there brains look like.

My sympathies to you. The sensory stuff sounds just awful.

My symptoms have worsed since I had covid, and I've had symptoms I never had before. I used to have POTS and dysautonomia but none of the obvious auto-immune symptoms. Now I am getting a fever with swollen glands every couple of weeks; it lasts about 3-4 days, I need another 2-3 to recover. On top of my normal symptoms (pain, fatigue, brain-fog—you know the list) I'd say I've gone from a 6 to a 4 on the function scale (out of 10). My covid bout wasn't too bad, like yours, and I really wasn't expecting this!