Thread by @NickAnderegg

Let me start by saying AAAAAAAAAAAAAAAAAAAAAA.

Turns out SARS-CoV-2 RAPIDLY infects the NERVOUS SYSTEM long BEFORE it even enters the bloodstream.

These findings have huge implications! Here's an analysis of the study, written for a general audience. (Sorry in advance!)

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Overall, it's pretty extensive: They examined the productivity of neuronal infection in multiple animal models and multiple neuronal cell cultures, and found productive neuronal infection across the board.

It's also a long one, but we'll pick up the pace as we go!

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So, as you may already know, neurological symptoms are actually VERY common when it comes to COVID, with several different types of neurological issues being notable features of Long COVID. There's seriously so much evidence beyond these 13 citations!

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The ability of SARS-CoV-2 to invade the nervous system is not news on its own! (For example, see )

This study, instead, looks at all the other possible routes of neuroinvasion that have been somewhat neglected UNTIL now!

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pandemicpatients.org/home/covid-19-…

Their goal was to "determine if infection of the PNS [peripheral nervous system] preceded and contributed to CNS [central nervois system] infection," by examining the mucosal tissues with lots of PNS connections.

[Spoiler: Turns out, it super-duper does.]

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In the first reported study, they did a comparison between:
- "wild type" mice (WT)
- human ACE2-expressing mice (hACE2)

which were exposed to the SARS-CoV-2 variant from 2020—specifically, the isolate from one of the first cases detected in the US! (So, first wave.)

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The mice were innoculated with SARS-CoV-2 (by spraying it up their noses), then letting it run its course, with various diagnostic tests along the way.

They confirmed low levels of blood and lung infection at 3 and 6 days post-infection in both groups, as expected!

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The Trigeminal Ganglia (TG) connects *sensory nerves* from the mouth and nose to the brainstem.

The Superior Cervical Ganglia (SCG) is part of the *sympathetic nervous system*, connecting glands (saliva, tears) and head/brain vasculature to the CNS.

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Before we get to the results, I want to pause to note that if you are reading this, what happened to these mice has DEFINITELY NOT happened to you to anywhere near the same extent! If the mice weren't euthanized for dissection, they would have ALL died from the infection.

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SARS-CoV-2 was found in both TGs and SCGs, in BOTH groups—hACE2 mice AND WT mice.

In both group, the viral concentration increased over time, suggesting there was active viral genome replication occurring.

But, hACE2 neurons in the SCG, in particular, basically fell apart.

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In the hACE2 mice infected with SARS-CoV-2, about 97% of the neurons in the SCG were positive for the nucleocapsid (N) protein, "showing substantial pathology with vacuolated neurons and loss of ganglionic architecture."

So... not great.

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If you're now wondering about the spike protein: They found it in both ganglia, in hACE2 and WT groups!

However, infectious virus "was not detected in SCGs." Why?

"SARS-CoV-2 may have produced such significant cytotoxicity that production of viral progeny was impossible."

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That's a very scientific way of saying "it so thoroughly damaged the cells of the hACE2 Superior Cervical Ganglia that they kinda stopped being cells."

Thus, they conclude "TGs may serve as a route of CNS invasion" AND "neuroinvasion can occur independently of hACE2."

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Now that we've have the conceptual groundwork for what they're doing, we can go a bit quicker! I'm also going to stop writing out terms from the excerpts that are identified by acronyms, for brevity.

Next up, nerves for sensory information from limbs and internal organs!

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The LS-DRG is a PNS nerve cluster that "conveys sensory information (pain, pressure, position) from the periphery [limbs] and internal organs" to the LS-SC. The LS-SC is the part of the spinal cord where the peripheral nerve bundle connects to the CNS.

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Viral RNA was found in both LS-DRG and spinal cord, for both the hACE2 and WT mice.

The nucleocapsid protein was found in about 42% of LS-DRG neurons of hACE2 mice (24% for WT mice), and results for the spike protein were similar.

Satellite glial cells were also infected.

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Furthermore, they stained the spinal cord nerve cells and found a diffuse signal (not pictured).

"These data further demonstrate that PNS sensory neurons, as well as functionally connected neurons in the spinal cord, are susceptible to infection with SARS-CoV-2."

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Next, they looked at multiple brain regions (olfactory bulb, hippocampus, cortex, brainstem, and cerebellum).

They found viral RNA in all of them at 3 days post-infection, which then increased at 6 dpi.

The quantities of RNA in WT mice suggests ACE2-independent spread!

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Viral RNA and infectious virus were recovered from allll over the brains of both the hACE2 mice and (unexpectedly) the WT mice. They note that "viral RNA and the infectious virus were readily recoverable throughout WT brains"

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They conclude: "These results indicate that viral invasion and replication in the brain is not uniform, that the highest concentrations of virus are found in areas connected to the trigeminal and limbic systems, and that neuroinvasion is not solely dependent on hACE2..."

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Then, when they cultured the virus in neurons, they found infectious virus in the PNS sensory neurons, but not the autonomic neurons. This suggests that while autonomic neurons can be infected, they can't produce viral progeny.

Weird!

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Headline result: Does neuroinvasion of the PNS/CNS occur BEFORE the virus enters the bloodstream?

"By 18 [hours post-infection], although no viral RNA was detected in blood..., viral RNA was detected in all PNS ganglia and the majority of functionally connected CNS tissues"

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Then, at 42 hours post infection, the virus was still only found in the blood of a single hACE2 mouse, but there was increased viral RNA in the brain.

They replicated this study with a different animal model and got roughly the same results. This is thorough work!

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In the other animal model (hamsters), they conclude "neuroinvasion occurs rapidly..., is mediated by invasion of and transport along neurons, can occur independent of hACE2, and functionally impacts PNS sensory neurons, resulting in allodynia [pain from mild stimulation]."

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So what's the deal with non-hACE2 mice and hamsters getting infected? How is infection occurring independent of ACE2 receptors?

It just uses a different receptor to enter the cells: NRP-1.

It was previously known SARS-CoV-2 could use this receptor, and this supports that!

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Three big takeways:

1. SARS-CoV-2 can infect PNS neurons very rapidly after exposure, long before it gets near the bloodstream
2. The virus can move from PNS to CNS via axonal transport before it enters the blood
3. NRP-1 is how it does it independently of hACE2

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But here's the thing: Not ALL of these results are new. Some of them are just now being tied together neatly in this one study.

IMO, widespread short-sighted research practices made these conclusions take so long to reach. The ball is being dropped with autopsy studies!

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At this point, we are only BEGINNING to understand the impact COVID can have on the brain and nervous system.

You know what we DO understand well? How to filter airborne particulate! Wear a filtering respirator in shared air to protect yourself.

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Neuroinvasion "is not a rare event following SARS-CoV-2 infection" and occurs "well before the onset of symptomatic disease."

Now that the pandemic has been DECLARED over, COVID-19 is transitioning to "an endemic disease associated with long-term neurological sequelae."

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Endemic doesn't mean "good." It just means "now we're stuck with it."

Just sit there and stew in that for a minute: "an endemic disease associated with long-term neurological sequelae."

You can ignore it, but it doesn't give a shit what you think! You're just an incubator.

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This paper, however, is pretty damn solid! It really ties a LOT of different lines of research together.

Published today (July 28, 2024) in IJMS, open access:

31/31mdpi.com/1422-0067/25/1…

Even if you're specifically familiar with it in the context of SIRS, it doesn't change the fact that "viremia" literally means, BY DEFINITION, "presence of viruses in the blood."

Your "correction" is 45 years out of date.



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meshb.nlm.nih.gov/record/ui?ui=D…

Believe me, I went deep on looking for flaws in this one! My day yesterday was just picking apart this paper and cross-referencing every claim that seemed too convenient or tidy. Unfortunately, they did their due diligence and it's pretty solid!

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Moreover, there's not really anything new about this study *methodologically*!

When the references are solid, the stats are solid, and the method is basically just "we followed manufacturer instructions for this protocol x10," there's not much else to poke at for flaws!

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Yup, it's EXACTLY why!

Anosmia is frequently a result of damage to the olfactory nerve:

And several issues people have in LC (including with chewing!) also aligns with the trigeminal nerve:

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ncbi.nlm.nih.gov/books/NBK55605…
ncbi.nlm.nih.gov/books/NBK48228…

Oh, yeah... wasn't there some quack on here a few days ago who was saying there's no "disease mechanism" that could explain why chewing is difficult in LC?

It must be humiliating to be a doctor and not be familiar with the concept of trigeminal nerve dysfunction!

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Here is the entire thread about "SARS-CoV-2 Rapidly Infects Peripheral Sensory and Autonomic Neurons, Contributing to Central Nervous System Neuroinvasion before Viremia" on a single page: readwise.io/reader/shared/…