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Persistent SARS-CoV-2 Infection in the Body and the Brain



From the preprint "SARS-CoV-2 infection and persistence throughout the human body and brain".

Yes the virus is present in your eyes, nerves, heart, brain, you name it from very early on in the acute infection AND it replicates in those cells AND it is present in those cells for up to 230 days. This has to be a dream paper for validating Long Covid!! Especially those with persistent cognitive dysfunction and other neurological sequelae.

Please note trigger warning - sensitive subject matter


Summary for fatigues and brain foggers

  • COVID-19 is known to cause multi-organ dysfunction in acute infection, with prolonged symptoms experienced by some patients, termed Post-Acute Sequelae of SARS- CoV-2 (PASC) or Long Covid.

  • However, the burden of infection outside the respiratory tract and time to viral clearance is not well characterized, particularly in the brain

  • The researchers performed complete autopsies on 44 patients with COVID-19 to map and quantify SARS-CoV-2 distribution, replication, and cell-type specificity across the human body, including brain, from acute infection through over seven months following symptom onset.

  • They showed that SARS-CoV-2 is widely distributed, even among patients who died with asymptomatic to mild COVID-19, and that virus replication is present in multiple pulmonary and extrapulmonary tissues early in infection.

  • They detected persistent SARS-CoV-2 RNA (replicating virus) in multiple anatomic sites, including regions throughout the brain, for up to 230 days following symptom onset.

  • Despite extensive distribution of SARS-CoV-2 in the body, they observed a lack of inflammation or direct viral damage outside of the lungs.

  • This data proves that SARS-CoV-2 causes systemic infection and can persist in the body for months.


Introduction

Some survivors experience Post-Acute Sequelae of SARS-CoV-2 (PASC) – also known as Long COVID—with cardiovascular, pulmonary, and neurological manifestations with or without functional impairment. While autopsy studies of fatal COVID-19 cases support the ability of SARS-CoV-2 to infect multiple organs extra-pulmonary organs often lack evidence of direct virally-mediated injury or inflammation.


Why did they do the research?

  1. To see where the virus was found outside the respiratory tract

  2. To see what extra-pulmonary cells were infected with the virus and whether these cells supported viral replication

  3. To see if the virus persisted in extra-pulmonary tissues


What did they do?

They performed extensive autopsies on a diverse population of 44 individuals who died from or with COVID-19 up to 230 days following initial symptom onset. They looked for SARS-CoV-2 in the cells using PCR and other techniques.


They looked at the respiratory tract, cardiovascular system, lymphoid tissue, the gastrointestinal tract, the renal tract, endocrine tissue, the reproductive system, muscle, skin, eye and adipose tissue, the peripheral nerves and the brain.


What did they find?

SARS-CoV-2 RNA was detected in all 44 cases and across 79 of 85 anatomical locations


In early cases the highest amount of virus was found in the respiratory tract but even in some early cases it was found in EVERY tissue group apart from the reproductive system.



Figure 1. Distribution, quantification, and replication of SARS-Cov-2 across the human body and brain. The heat map depicts the highest mean quantification of SARS-CoV-2 RNA (N) via ddPCR present within the tissues of eleven COVID-19 autopsy patients who underwent whole body and brain sampling. Patients are aligned from shortest to longest duration of illness (DOI) prior to death, listed at the bottom of the figure, and grouped into early (≤14 days), mid (15-30 days), and late (≥31 days). Tissues are grouped by tissue category beginning with the respiratory tract at the top and central nervous system at the bottom. Viral RNA levels range from 0.002 to 500,000 N gene copies per ng of RNA input, depicted as a gradient from dark blue at the lowest level to dark red at the highest level. Tissues that were also positive for sgRNA real-time RT-PCR are shaded with black vertical bars.



The mean SARS-CoV-2 N gene copies/ng RNA (ie replicating virus) detected from tissues in each grouping among early cases are as follows:

  • 9000 across respiratory tissues

  • 40 across cardiovascular tissues

  • 30 across lymphoid tissues

  • 25 across gastrointestinal tissues

  • 13 across renal and endocrine tissues

  • Less than 0.5 across reproductive tissues

  • 30 across muscle, peripheral nerve, adipose, and skin tissues

  • 60 across ocular tissues

  • 33 across brain tissues


As expected the later the case the less SARS-CoV-2 DNA and mRNA was found.

BUT several mid and late cases had high levels (≥5 N gene copies/ng RNA input) detected among multiple tissues:




Also persistence of low-level SARS-CoV-2 RNA (0.0004 to <0.5 N gene copies/ng RNA input) was frequently detected across multiple tissue categories among all late cases, despite being undetectable in plasma.

Notably, SARS-CoV-2 RNA was detected in the brains of all six late

cases and across most locations evaluated in the brain in five of these six, including Patient 42 who died at Day 230.


Overall, SARS-CoV-2 RNA (replicating virus) was detected in the:

  • Respiratory tissue of 98% cases

  • Cardiovascular tissue of 80% cases

  • Lymphoid tissue of 86% cases

  • Gastrointestinal tissue of 73%

  • Renal and endocrine tissue of 64% cases

  • Reproductive tissue in 42% cases

  • Muscle, skin, adipose, and peripheral nervous tissue in 68%

  • Ocular tissue and humors of 58% cases

  • Brain tissue in 90% of cases


What did they conclude?


  1. SARS-CoV-2 disseminates across the human body and brain early in infection at high levels

  2. Virus replication at multiple extrapulmonary sites during the first week following symptom onset.

  3. They detected RNA in at least one tissue in over half of cases beyond Day 14, suggesting that prolonged viral replication may occur in extra- pulmonary tissues as late as Day 99.

  4. They demonstrate conclusively that SARS-CoV-2 is capable of infecting and replicating within these tissues colon, lymphoid tissue, eye, spleen and lymph nodes.

  5. The results collectively show while that the highest burden of SARS-CoV-2 is in the airways and lung, the virus can disseminate early during infection and infect cells throughout the entire body, including widely throughout the brain. This occurs very early on in the infection.

  6. The findings suggest viremia (virus in the blood) leads to body-wide dissemination, including across the blood-brain barrier, and viral replication can occur early in COVID-19, even in asymptomatic or mild cases.

  7. While the respiratory tract was the most common location in which SARS-CoV-2 RNA tends to linger, ≥50% of late cases also had persistence in the myocardium (heart), thoracic cavity (chest) lymph nodes, tongue, peripheral nerves, ocular tissue, and in all sampled areas of the brain, except the dura mater.

  8. Interestingly, despite having much lower levels of SARS-CoV-2 in early cases compared to respiratory tissues, we found similar levels between pulmonary and the extrapulmonary tissue categories in late cases. This less efficient viral clearance in extrapulmonary tissues is perhaps related to a less robust innate and adaptive immune response outside the respiratory tract.

  9. The data suggests that SARS-CoV-2 can replicate within tissue for over 3 months after infection in some individuals, with RNA failing to clear from multiple compartments for up to Day 230. This persistence of viral RNA and sgRNA may represent infection with defective virus, which has been described in persistent infection with measles virus –another single-strand enveloped RNA virus—in cases of subacute sclerosing panencephalitis.

  10. The mechanisms contributing to PASC/ Long Covid are still being investigated; however, ongoing systemic and local inflammatory responses have been proposed to play a role. This data provides evidence for delayed viral clearance, but do not support significant inflammation outside of the respiratory tract even among patients who died months after symptom onset.

  11. Understanding the mechanisms by which SARS-CoV-2 persists and the cellular and subcellular host responses to viral persistence promises to improve the understanding and clinical management of PASC/Long Covid.


Reference

https://www.researchsquare.com/article/rs-1139035/v1?fbclid=IwAR1cgKw7FxFJaARC8mD5W3KOXxFWCPUegj_9EM0eQFLnm-DEK9_zHjxIBhg

















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