Vagus/Olfactory Nerve Trafficking, Brainstem and Inhibitory Neuron Death, the Spike Protein and Sudden Cardiac Death

Two Mechanisms of Spike Protein Sudden Cardiac Death: Myocarditis and Neurogenic

Potential routes of SARS-CoV-2 entry into the CNS (created using BioRender). A potential entry route of SARS-CoV-2 into the CNS could be via the olfactory epithelium. Another pathway of entry could be by infection of the brain capillary endothelium (hematogenous pathway). Immune responses to viral infection may result in disruption of the blood brain barrier, resulting in the creation and maintenance of an inflammatory environment in the CNS.

The saying goes “All roads lead to Rome.” However, in the case of the Spike Protein of SARS-CoV-2, one might say “All roads lead to the Brainstem.” If we look at the two major routes of infection, digestive and respiratory, we can observe that direct access to the brainstem is achieved by the Spike Protein in both cases.

The olfactory route is described in the above graphic. Regarding digestive system entry of the Spike Protein to the brainstem the article goes on to state (please note confirmation of my hypothesis that the Spike is traveling via retrograde axonal transport, this obviously has implications far beyond the vagus nerve itself):

Other cranial nerves, such as the vagus, glossopharyngeal, and trigeminal nerves, may also be potential routes for the virus to enter the brain via retrograde axonal transport. These nerves get exposed to the virus during the course of infection. The vagus nerve, which is connected to the gastrointestinal tract as a part of the enteric nervous system, has an abundance of ACE-2 and NRP 1 receptors. Some studies have suggested that the virus can access the CNS through peripheral fibers of the vagus nerve in the lung, similar to influenza virus. A study examining brainstem neuropathology demonstrated the presence of SARS-CoV-2 in vagus nerve fibers by the use of immunohistochemistry (IHC).

SARS-CoV-2 and the nervous system: current perspectives
https://link.springer.com/article/10.1007/s00705-023-05801-x

Yet, how do we know that it is the Spike Protein which is causing the death of neurons?

To further determine the type of programmed cell death, we examined the presence of necroptotic, ferroptotic, and senescent cells. The cell necroptosis markers phospho-MLKL (mixed lineage kinase domain-like) and phospho-RIPK3 coexisted in spike protein-positive cells. Similarly, the two cell ferroptosis markers TfR1 (transferrin receptor) and ASCL4 (long-chain fatty acyl-CoA synthetase 4) were expressed in cells with positive spike protein signals. Because the cytokine associated with SARS-CoV-2 may trigger the cellular senescence program, we detected the senescence marker DPP4 (dipeptidyl-peptidase 4) in a subset of spike protein-positive cells. There were negligible double spike protein- and TfR1- or p-RIPK3-positive cells in the COVID-19 Alzheimer’s case. These findings suggest that SARS-CoV-2 leads to cell death and senescence through multiple pathways.

In addition to the brainstem, inhibitory neurons are also infected with the Spike Protein.

In the same region, both GABAergic inhibitory neurons (GAD65-positive) and glutamatergic excitatory neurons (glutamine synthetase-positive) contained SARS-CoV-2 spike protein staining signals.

SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology
https://www.biorxiv.org/content/10.1101/2022.01.31.478476v2.full

And, we know the Spike is, indeed, found in the brainstem.

Thus, either pathological immune responses or SARS-CoV-2 invasion of the brainstem was suspected. Another autopsy study has isolated  brain sections from 16 victims of COVID-19 and found concentrated SARS-CoV-2 RNA (>5 copies/mm3) in three sections from the olfactory nerves and the brainstem’s medulla. More convincingly, in another autopsy study of deceased COVID-19 patients, SARS-CoV-2 RNA and proteins (nucleocapsid or spike) were detected in 50% and 40% of brainstem samples, respectively. Similarly, another autopsy study has found SARS-CoV-2 RNA and spike proteins in the olfactory mucosal-neuronal junction and brainstem’s medulla in 67% and 19% of samples, respectively. In sum, these autopsy studies have provided evidence for SARS-CoV-2 tropism from the olfactory system into the brainstem.

Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874499/

Ultimately, when the brainstem is damaged enough, sudden cardiac death will follow.

There is now substantial evidence that higher brain function (cortex), the brain stem and autonomic nerves affect cardiac electrophysiology and arrhythmia, and that these may function as an interactive system. The roles of mental stress and emotion in arrhythmogenesis and sudden cardiac death are no longer confined to the realms of anecdote. Advances in molecular cardiology have identified cardiac cellular ion channel mutations conferring vulnerability to arrhythmic death at the myocardial level. Indeed, specific channelopathies such as long QT syndrome and Brugada syndrome are selectively sensitive to either sympathetic or vagal stimulation. There is increasing evidence that afferent feedback from the heart to the higher centres may affect efferent input to the heart and modulate the cardiac electrophysiology.

Heart–brain interactions in cardiac arrhythmia
https://heart.bmj.com/content/97/9/698.abstract

All of this hearkens back to a paper from May of 2021.

Overall, brainstem neuropathological involvement agrees with neurophysiological brainstem abnormalities and neuroradiological evidence describing rhombencephalitis in COVID-19. Clinical, neuropathological, neurophysiological and neuroradiological data therefore indicate that severe COVID-19 involving the central nervous system targets the brainstem. Neuropathologic evidence showing SARS-CoV-2 in the brainstem and medullary damage in the respiratory center areas strongly suggests that the pathophysiology of COVID-19 related respiratory failure includes a neurogenic component.

Brainstem neuropathology in two cases of COVID-19: SARS-CoV-2 trafficking between brain and lung
https://link.springer.com/article/10.1007/s00415-021-10604-8

Inhibitory neuron death can also contribute to sudden cardiac death, especially if the vagus nerve is also involved. What does this tell us? That in addition to the sudden cardiac deaths due to myocarditis, there are also sudden cardiac deaths with a neurogenic component. It is not just athletes under performance stress or the very fit and young that are dying suddenly.

My greatest concerns with this finding? What does this mean for all of us? Long term? With repeated infections/exposures?

I will be working, as always, on solutions. Immense thanks for your continued support.