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SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications

Discussion in 'Long Covid research' started by SNT Gatchaman, Apr 6, 2023.

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  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19
    Zhouyi Rong; Hongcheng Mai; Saketh Kapoor; Victor Puelles; Jan Czogalla; Julia Schaedler; Jessica Vering; Claire Delbridge; Hanno Steinke; Hannah Frenzel; Katja Schmidt; Oezuem Sehnaz Caliskan; Jochen Martin Wettengel; Fatma Cherif; Mayar Ali; Zeynep Ilgin Kolabas; Selin Ulukaya; Izabela Horvath; Shan Zhao; Natalie Krahmer; Sabina Tahirovic; Ali Oender Yildirim; Tobias Huber; Benjamin Ondruschka; Ingo Bechmann; Gregor Ebert; Ulrike Protzer; Harsharan Singh Bhatia; Farida Hellal; Ali Erturk

    Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been associated mainly with a range of neurological symptoms, including brain fog and brain tissue loss, raising concerns about the virus's acute and potential chronic impact on the central nervous system.

    In this study, we utilized mouse models and human post-mortem tissues to investigate the presence and distribution of the SARS-CoV-2 spike protein in the skull-meninges-brain axis.

    Our results revealed the accumulation of the spike protein in the skull marrow, brain meninges, and brain parenchyma. The injection of the spike protein alone caused cell death in the brain, highlighting a direct effect on brain tissue. Furthermore, we observed the presence of spike protein in the skull of deceased long after their COVID-19 infection, suggesting that the spike's persistence may contribute to long-term neurological symptoms. The spike protein was associated with neutrophil-related pathways and dysregulation of the proteins involved in the PI3K-AKT as well as complement and coagulation pathway.

    Overall, our findings suggest that SARS-CoV-2 spike protein trafficking from CNS borders into the brain parenchyma and identified differentially regulated pathways may present insights into mechanisms underlying immediate and long-term consequences of SARS-CoV-2 and present diagnostic and therapeutic opportunities.

    Link | PDF (Preprint: BioRxiv)
     
    SNT Gatchaman, Apr 6, 2023
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  2. Hutan

    Hutan Moderator Staff Member

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    That's a first sentence that might raise a few eyebrows from respiratory physicians, I'm not sure that that is what they meant.

    I find this quite interesting. Viral persistence with long periods of latency would be a straightforward answer to the question 'what causes ME/CFS?'. I think it is possible.

    A summary of previous evidence for persistence:

    Whole body distribution of spike S1 protein in a mouse model
    They fluorescently-labelled spike protein that binds to the mouse version of the ACE receptor and injected it into mice. After 30 minutes, they looked for the fluorescence. It sounds as though it was mostly in or very close to the blood vessels, as we might expect, but also in testes, ovaries and the brain and spinal column, skull marrow niches, in the channels connecting the skull marrow to the meninges, and other bone marrow niches (e.g.in the tibia and femur). Control proteins of the spike protein that binds to the human ACE receptor and a flu protein were not distributed throughout the body like this.

    So, that tells us that the spike protein can get into most parts of mice pretty quickly, although it doesn't tell us about persistence.
     
    Hutan, Apr 6, 2023
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  3. Hutan

    Hutan Moderator Staff Member

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    SARS-CoV-2 infection in the human skull, meninges, and brain
    They found viral spike protein in the skull marrow niches, skull marrow channels, and meninges of 17 patients who died during an acute Covid-19 infection and no viral spike protein in samples from control patients. They suggest that the spike protein leaked into the bone marrow. They also found spike protein in the perinuclear space of meningeal cells and around neurons in the brain cortex.

    They identified SARS-coV2 RNA and nucleocapsid protein in about half each of the skull samples and meninges samples.

    So, very good evidence that the the virus and viral proteins are getting into human skulls and meninges, but still not evidence that they persist.
     
    Hutan, Apr 6, 2023
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  4. Hutan

    Hutan Moderator Staff Member

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    So far, this is a nicely written paper - it's quite straightforward for such technical things.
    From a German team.

    Proteomics profiling of COVID-19 patient skull marrow, meninges, and brain samples
    They compared the proteins in the skull and brain tissues of 10 Covid-19 patients and 10 non-Covid patients, reporting similar sets of proteins within each group, but less similarities between the groups.
    Here's the PCA analysis of the Covid and non-Covid protein sets
    Screen Shot 2023-04-06 at 7.28.16 pm.png
    When they looked at the proteins that were different in the Covid-19 nonsurvivors' bone marrow, meninges and brain cortex, they found a whole lot associated with a viral infection and immune responses. There is detail there that looks like novel findings, potentially useful for managing acute infections. They do mention NDUFA proteins, noting loss or dysfunction of these problems can impair mitochondrial function, suggesting this might be relevant to the symptom of chronic fatigue.

     
    Hutan, Apr 6, 2023
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  5. Hutan

    Hutan Moderator Staff Member

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    Spike S1 protein triggers proteomics changes in the mouse skull marrow, meninges, and brain
    They did similar sorts of things with the mice, looking at proteins in the skull and brain tissues 3 days after the injection of the spike protein or controls. As in the human tissues, they found proteins involved in immune responses, namely NETs formation, neutrophil degranulation and PI3K-AKT pathways. In the mouse brain cortex exposed to the spike protein, they found proteins associated with neurodegeration. NDUFA makes an appearance.
    Spike protein from the skull marrow leads to brain cortex neuronal injury
    They microinjected the spike protein directly into the mice skull marrow. The spike protein reached the meninges and brain parenchyma within 30 minutes. They found brain cell death and neuronal injury 3 and 28 days after injection.

    Spike protein persists in the human skull marrow
    Here's the persisting bit.
    They looked for spike protein in the skulls of 34 people who died from non-COVID related causes during the pandemic. They found spike protein in 10 of the people. It's inferred that these people were not testing positive to Covid-19 at the time they died.
     
    Hutan, Apr 6, 2023
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  6. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    From the above I am not clear that any of this explains anything relevant either to LongCovid or ME?

    I am afraid that a paper with Skull-Meninges-Brain Axis in the title says to me 'We are a group of people studying brainish things who know absolutely nothing about the rest of biology and will tell you about the things we found that we wanted to find.' The skull marrow has nothing to dow with brain as far as I know. There is essentially no barrier between blood and bone marrow compartments. There is bone and dense fibrous tissue between marrow and CSF.
     
    Jonathan Edwards, Apr 6, 2023
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  7. Hutan

    Hutan Moderator Staff Member

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    Just as aside, it's a bit sobering to read about a mutation in the Covid virus that makes it infect mice. I'm not sure if that's just a lab thing or if it is out there in wild mice. The virus must be mutating its way through a whole lot of species.

    From the discussion: they talk about significant brain tissue loss in mild Covid-19 cases. I'm not sure about the strength of evidence for that.

    Do you not find the idea of skull meninges channels connecting the skull marrow to the meninges convincing? Are the channels only vascular, so that there is still a blood brain barrier?
     
    Hutan, Apr 6, 2023
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  8. Hutan

    Hutan Moderator Staff Member

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    It sounds to me as though these channels aren't vascular; a very recent finding
    https://news.harvard.edu/gazette/st...s-key-to-detection-of-brain-infection-injury/
     
    Hutan, Apr 6, 2023
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  9. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    SNT Gatchaman, Apr 6, 2023
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  10. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I am sure there is still a blood brain barrier. Skull marrow may be close to brain but then sternal marrow is close to lung - I doubt it is of any relevance to anything. If there is viraemia - which there has to be pretty much to get the virus from your nose to everywhere else, then local routes are probably irrelevant. Virus in brain may spill out into CSF but then CSF is really just the interstitial fluid of brain (or near enough).
     
    Jonathan Edwards, Apr 6, 2023
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  11. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Frankly I think this is just a manifestation of the way research is now done by people with little understanding of general principles of things like cell and fluid flux and inflammation. It makes absolutely no sense to suggest that there is some special traffic c between CSF and skull marrow. No doubt you can demonstrate channels and fluid or solute transit but, like the so-called discovery of brain lymphatics I don't see this as changing our understanding significantly. Everyone now is trying to make their own microfield seem important.

    Why on earth would CSF 'regulate' bone marrow niches? What is 'regulate' supposed to mean here?
     
    Jonathan Edwards, Apr 6, 2023
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  12. Sean

    Sean Moderator Staff Member

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    I think there is often a confusion in research between regulates (controls), and interacts with (affects).
     
    Sean, Apr 7, 2023
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  13. EndME

    EndME Senior Member (Voting Rights)

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    EndME, Nov 29, 2024
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  14. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    I don't consider this very compelling, this mouse model is simply too different to the human disease and I don't think the findings are relevant.
     
    Snow Leopard, Nov 30, 2024
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  15. Dolphin

    Dolphin Senior Member (Voting Rights)

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    Press release:
    Long COVID: SARS-CoV-2 spike protein accumulation linked to long-lasting brain effects

    Peer-Reviewed Publication

    Helmholtz Munich (Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH))

    Researchers from Helmholtz Munich and Ludwig-Maximilians-Universität (LMU) have identified a mechanism that may explain the neurological symptoms of Long COVID. The study shows that the SARS-CoV-2 spike protein remains in the brain’s protective layers, the meninges, and the skull’s bone marrow for up to four years after infection. This persistent presence of the spike protein could trigger chronic inflammation in affected individuals and increase the risk of neurodegenerative diseases. The team, led by Prof. Ali Ertürk, Director at the Institute for Intelligent Biotechnologies at Helmholtz Munich, also found that mRNA COVID-19 vaccines significantly reduce the accumulation of the spike protein in the brain. However, the persistence of spike protein after infection in the skull and meninges offers a target for new therapeutic strategies.

    Continues at:
    https://www.eurekalert.org/news-releases/1066512

     
    Dolphin, Dec 3, 2024
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