SARS-CoV-2 invades the brain using the nerves

"One virus to trospim them all"

A few days ago, a rather illuminating paper was published I decided to let it simmer for a while, and the moment I thought about covering it, an article of bigger significance happened, where authorities found one of many clandestine biological labs, this particular instance in California.

Thus here we are. A massive point of contention, one which I argued both in favor and against at different points in time, was the neurotropism of SARS-CoV-2 (tropism in simple terms meaning the capacity of the pathogen to enter X region of the body, neuro means the brain). It is uneditable the capacity of SARS-CoV-2 to induce neurological inflammation and damage at different levels, often correlated with the severity of infection, the debatable aspect was always the “how”. Does it get to the brain, does it not ? Directly, indirect, “bystander effect”, or the one I was most prone to accept, hit and run.

Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

Anosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Here, we assessed the clinical, olfactory and neuroinflammatory conditions of golden hamsters infected with the original Wuhan SARS-CoV-2 strain, its isogenic ORF7-deletion mutant and three variants: Gamma, Delta, and Omicron/BA.1. We show that infected animals develop a variant-dependent clinical disease including anosmia, and that the ORF7 of SARS-CoV-2 contributes to the induction of olfactory dysfunction. Conversely, all SARS-CoV-2 variants are neuroinvasive, regardless of the clinical presentation they induce. Taken together, this confirms that neuroinvasion and anosmia are independent phenomena upon SARS-CoV-2 infection. Using newly generated nanoluciferase-expressing SARS-CoV-2, we validate the olfactory pathway as a major entry point into the brain in vivo and demonstrate in vitro that SARS-CoV-2 travels retrogradely and anterogradely along axons in microfluidic neuron-epithelial networks.

Anosmia entails the loss of smell, something a complete loss of smell, as the introduction states it was a hallmark of a Covid infection, later to be correlated at some levels with a myriad of lingering symptoms, as to a degree a possible hint towards who could theoretically develop Long Covid, and this effect change overtime as variants mutated and changing their tropism to what I name “low-level tropism change”, meaning the virus still uses its favored receptor yet it changed the preferred “organs” and little roads it uses inside you.

The authors went to test and measure the extension of clinical disease in hamsters, their chosen and a good in vivo (living) model, finding what by now is a common trend, different variants present different degrees of disease severity, something I covered for the entirety of 2022 here. Correlated with the evidence to this point in time, the Wuhan strain is the most aggressive, followed by Gamma, Delta and the mildest one with a delayed manifestation of disease was Omicron/BA.1.

They go into detail on the gene expression of each variant, and its effect on olfactory function and lung disease, and repeating myself, following the known trend, Wuhan and Gamma being the most aggressive ones in either markers or symptoms, oddly enough Delta and Omicron/BA.1 were outliers in which they had no effect on “smell” dysfunction. The trend normalizes to Wuhan, Gamma, and Delta, followed by Omicron/BA.1 in regards to lung pathology.

Their next step was measuring the viral titer (number of infected cells) and amount of RNA load in the upper airways (nasal turbinates) and in the lower airways (lung), and infectious viruses were detected in both upper and lower airways regardless of variant, however as we are familiar by now, each variant had a different level, Gamma being the highest, Omicron/BA.1 being the lowest, however in the lungs, Delta has the highest viral load.

Each variant had a different inflammation-related gene expression which was “location” dependent. In the lung, they all share a similar response yet the Wuhan had the highest upregulation among the variant, in the upper airways (nasal turbinates), once again Wuhan had more of Ifn-β and Il-6, and Omicron/BA. 1 the lowest levels.

In their next step, and the reason we are discussing this matter, the authors attempted to find the effect of infection on the factory bulbs, therefore categorizing neuroinvasion and neuroinflammation.

They created 3 recombinant SARS-CoV-2 strains, recombinant meaning adding something not common or ever found in the “natural” virus, the viruses were modified to produce nanoluciferase, an enzyme derived from fireflies, but engineered to be minuscule, it is extremely useful for visualizing and tracking biological changes. The variants created were Wuhan, Wuhan without ORF7, and Delta.

They did their imaging with the animals both live and after being euthanized. The lungs showed a similar “glow” for all 3 viruses. The most intense glowing signals in the brain came from the olfactory bulbs. When they measured the intensity of the signal specifically in the olfactory bulbs, they found that Wuhan_nLuc had higher intensity compared to Delta_nLuc. However, when they considered the entire ventral (bottom) area of the brain, Delta_nLuc showed higher intensity. Wuhan/ΔORF7ab_nLuc had intermediate values.

The olfactory bulbs were the main infected structures in the brain.

The next step was elucidating if SARS-CoV-2 could infect neurons and move inside them through axons (long nerve fibers projected from nerve cells, neurons is the fancy term for nerve cells hehe), and here the authors point out the same I did a few minutes ago, the conflicting results of previous studies if the virus could directly infect neurons or not.

And it did, by creating a co-culture using both human stem cell-derived neurons and A549 hACE2-TMPRSS2 cells, an epithelial cell line for experiments they found that they could easily be infected by SARS-CoV-2. For clarification A549 is the cell line, a lung one, h stands for Human, ACE2, and TMPRSS2 are both receptors, adding TMPRSS2 makes it much easier for SARS to infect cells.

Using this method, the two cell types created networks, and the authors were able to track the movement of the “glowing virus”, and they observed the virus could travel both retrogradely and anterogradely in the axons. In plain English, the virus was able to move left to right, right to left between the nerve cells. Before adding my own observations and considerations, I will leave the author’s closing remarks.

Despite this shared neuroinvasiveness via the olfactory bulbs, disease profile and airways responses are quite dependent on the SARS-CoV-2 variant. Indeed, we show that all VoCs can infect golden hamsters and promote lung inflammation, including Omicron/BA.1 differently from other reports^19,50, probably due to infectious doses or viral isolates. A “variant-effect” in the clinical presentation and in the tissue-related inflammation was evident, with disease severity presenting the following order: SARS-CoV-2 Wuhan > Gamma > Delta > OmicronBA.1, which supports the hypothesis that Omicron/BA.1 evolution has resulted in a tropism more restricted to the upper respiratory tract, thereby causing a less severe clinical disease^10,51,52,53. Although with different severities, neuroinvasiveness, neurotropism and neurovirulence³² seem to be conserved features among SARS-CoV-2 variants. Indeed, the data presented herein give support to the neuroinvasive ability of SARS-CoV-2, as besides detection of viral RNA and isolation of infectious virus from the olfactory bulbs, we could clearly observe SARS-CoV-2 infected neurons in the brain of hamsters by light sheet microscopy. Nevertheless in hamsters, unlike what has been reported in K18-hACE2 mice which ACE2 expression pattern is non-physiological and ectopic³⁹, detection of SARS-CoV-2-infected cells was restricted to the olfactory bulbs, without evidence of brain vasculature remodeling nor virus associated with blood vessels.

What is the significance of what was discussed here ?

A simplified map for visual learners. (Open into another tab because it has a somewhat big resolution)
These are but a minuscule aspect of the potential long-term negative impact of the virus being able to travel through axons, and infect neurons.

By possessing evidence demonstrating that SARS-CoV-2 can directly get inside the brain, it helps us understand a myriad of the damage the virus did, and potentially forecast the long-term dysfunction it may cause.

My Twitter name change is explained in the comments of this article.

Uncovering SARS-CoV-2 infection of neurons and especially its capacity to travel via axons helps us understand the mechanism behind the many neurological complications observed in Covid-19 patients, mainly moderate and severe patients, how some post-mortem observed virus in the nervous system, it helps explain cognitive and neurological dysfunctions. It helps us find a mechanism to explain persistent neurological symptoms in many people, even months after an acute or severe infection. As I wrote recently, most of what SARS-CoV-2 will induce now will be long-term problems, similar to influenza, where damage, dysfunction, and autoimmunity stack over time, but I got a (mathematically based) feeling it will be faster to observe in SARS-CoV-2 case.

But especially pertinent is the potential for SARS-CoV-2 to form viral reservoirs in the nervous system and cause long-term nervous and neurological dysfunction, the second, nervous system and autonomic dysfunction being observed and pertinent among many Long Covid and “Long Vaccine” patients. I wrote about SARS-CoV-2 and the brain extensively, and could go on and on, but if there is something you should read is the following.

The Spike protein and its impact in the cholinergic system

The “stalk” of the Spike Protein is conserved among all current variants and previous ones, it is present in the vaccine and especially of interest in all highly immune evasive, extremely competent in replication (above measles levels of replication and infection) Omicron variants (XBB).

Its impact on the cholinergic system is underappreciated but highly impactful and significant to everyone. Do you know what else lies latent in neurons and in the nerve system ? The family of viruses known as Herpes Viruses.

This is what I have been doing for a while, and this is what I suggest most people do for the foreseeable future as a just in case.

Thiamine or Benfotiamine is optional but I would highly suggest to add to your supplementation, I take 150 mg daily, some people thrive on 300-600 mg
Choline - 500 mg
GlyNAC - anything above 600 mg for BOTH After ANY RESPIRATORY INFECTION
Serrapeptase, AND Nattokinase - Any dosage you are comfortable with, also after each infection
Berberine and Metformin if you want to

I have yet to write about choline and its numerous benefit, especially in regard to what the virus may do long-term to some, but I will state this. I eat more eggs than most people I know, and even I have found benefit from taking Choline, it hits a lot of “boxes” of what the virus negatively impacts, and its secondary and tertiary effects, including from an endotoxin/LPS perspective.

Adding choline is at the very least worth the effort for 4-8 weeks.

This gives me leeway to write about other aspects of the virus in the coming weeks. I may write simplified, summarized “reviews” of many of my published articles for easier understanding too, something proposed by a subscriber.

Thank you for supporting and reading my work.