Unlike traditional influenza that leaves you feeling crappy for a few days and then clears up, Covid is displaying a whole new bag of tricks that we need to be concerned about. Particularly worrying are the long haul cases of Covid, where patients develop a number of symptoms that threaten to linger as chronic conditions. It is incredibly important that we focus on understanding exactly how Covid develops in the body and exactly which systems it attacks. Only in this way can we develop tools to combat the after-effects. Patients need to educate themselves and also be aware of potential symptoms for long-haul covid. Our brain is perhaps most at risk for affecting our quality of health, post covid.
Even if you’re not a medical expert, you must have heard the term Blood-Brain Barrier (BBB) and Central Nervous System (CNS) being used over and over in the last few months. Covid, we are told, can get into your head and I’m not referring to the mental stress of avoiding infection or being quarantined, but rather the real virus itself that causes covid. SARS-CoV2 can infect cells, nerves, and synapses in your brain.
This isn’t some superpower the covid virus possesses, but rather a trait shared by many of the coronaviruses that have preceded it. A growing body of literature demonstrates that neurotropism (a virus that is capable of infecting nerve cells) is a common feature of coronaviruses. Aside from common symptoms of covid, some neurological complications following SARS-CoV-2 infection include confusion, cerebrovascular diseases, ataxia, hypogeusia, hyposmia, neuralgia, and seizures. There are reports of brain edema⁵, partial neurodegeneration⁶, even encephalitis⁷ in severe cases of COVID-19.
Our brains are the computers that operate all the systems in our bodies. Breathing, blood flow, neural responses, pretty much everything your body can do or does, is controlled by the brain. For this reason, it’s well protected against invaders which may damage its delicate systems. Brain cells, unlike other cells in our body, can also not be replaced, so this is another good reason to try and keep the brain isolated and protected.
One method of protection for the brain is the Blood-Brain Barrier (BBB) mentioned earlier. It’s really good at keeping out viral invaders, but as we are discovering, it isn’t bulletproof. Certain viruses would seem to be able to cross this barrier. Let’s first establish what the SARS-CoV2 virus is and how it operates.
MOA and understanding the coronavirus family
Coronaviruses (CoVs) refer to a family of enveloped, positive-sense, single-stranded, and highly diverse RNA viruses. There are four genera (alpha, beta, gamma, and delta), among which α-coronavirus and β-coronavirus attract more attention because of their ability to cross animal-human barriers and emerge to become major human pathogens.
SARS-CoV-2 is the seventh member of the coronavirus family we’ve discovered. We know from previous evidence that these viruses infect humans. Of the seven, NL63-CoV, HKU1-CoV, 229E-CoV, and OC43-CoV, typically cause common cold symptoms, while SARS-CoV, MERS-CoV, and now the SARS-CoV-2 are responsible respectively for the SARS pandemic in 2002 and 2003, MERS in 2012, and the current COVID-19 pandemic.¹
SARS-CoV-2 is a betacoronavirus that shares almost 80% sequence identity with SARS-CoV and 50% sequence identity with MERS-CoV². Similar to SARS-CoV, SARS-CoV-2 binds to the enzymatic domain of the angiotensin-converting enzyme 2 (ACE-2) receptor exposed on the surface of several cell types, including alveolar cells, intestinal epithelial cells, endothelial cells, kidney cells, monocytes/macrophages, as well as neuroepithelial cells and neurons³.
After spike (S) protein binding to ACE-2 receptor, a subsequent cleavage by transmembrane protease serine 2, cathepsin, or furin, probably induces the endocytosis and translocation of SARS-CoV-2 into endosomes⁴ or a direct viral envelope fusion with host cell membrane for cell entry.
What we don’t know
There is no described direct mechanism of SARS-CoV-2 neuroinvasiveness currently in the medical literature. In simple English, we still don’t understand exactly how the virus manages to get through the body’s defenses to reach the brain. However, we do know that coronaviruses are not always limited to the respiratory system, but they can reach the central nervous system (CNS), inducing neurological impairments.
We have suspicions about the possible mechanisms the virus might be employing to breach our defenses but none have as yet been confirmed. As the covid virus shares much of its genetic makeup with the SARS and MERS viruses, perhaps we can look to studies of these viruses for clues, as both are known to also attack the CNS.
Breaching the castle walls
Essentially, there are three theories put forward currently to explain the CoV2 virus’s ability to reach the brain. All three mechanisms show merit and the issue is the subject of ongoing research across the planet. This matters because before you can successfully attempt to block a mechanism or ingress point, you need to figure out which one is being used.
Our starting point, as always, should be the known. It is known that coronaviruses are not always limited to the respiratory system, but they can reach the CNS, inducing neurological impairments. This neuroinvasive capacity is well established for most beta coronaviruses, including SARS-CoV⁸, MERS-CoV⁹, 229E-CoV¹⁰, OC43-CoV¹¹, and HEV¹².
The how isn’t that important to our understanding of the impacts of the virus on our brains, but for those interested in exploring the mechanisms further, here are the potential routes under investigation. If this isn’t your cup of tea, skip over it and scroll down to ‘What happening to our brains’.
Transcribial Route and Neuronal Transport Dissemination
Growing evidence shows that some coronaviruses first invade peripheral nerve terminals, then are anterograde/retrograde spread throughout the CNS via synapses, a well-documented neuroinvasive route for coronaviruses such as HEV67¹² and OC43-CoV¹¹. Among the peripheral nerves, the olfactory nerve is considered one of the strongest candidates for SARS-CoV-2 dissemination into the CNS because of its close localization to olfactory epithelium.
In the intranasal administration of SARS-CoV and MERS-CoV into transgenic mice, the viral CNS invasion is possible through the transcribial route, gaining direct access to the olfactory bulb, and then spreading to the thalamus and brainstem¹³. The exact mechanism of early CNS access is still unclear.
The covid virus may also be using peripheral nerves such as the vagus nerve, via which lungs and gut afferents reach the brainstem.
SARS-CoV-2 has been detected in COVID-19 patient feces. A recent in vitro study demonstrated the SARS-CoV-2 capacity to infect human intestinal epithelium¹⁴. The anterograde and retrograde viral transmission from duodenal cells to brainstem neurons has also been reported¹⁵. Therefore, it is possible that upon enterocyte SARS-CoV-2 infection, a further transmission to glial and neuronal cells within the enteric nervous system could reach the CNS via the vagus nerve.
Evidence regarding the enteric nervous system and the SARS-CoV-2 vagus nerve dissemination is almost null, and further research is required.
Hematogenous Route
The infection and damage of cells of epithelial barriers allow the virus entrance to the bloodstream and lymphatic system, spreading to multiple organs, including the brain¹⁶. The BBB is one of the most frequent viral entry routes to the CNS.
There are two possible mechanisms for SARS-CoV-2 spreading via this route, which involve the circulation of viral particles into the bloodstream: the infection and viral transcytosis across vascular endothelial cells, and the leukocytes infection and mobilization towards the BBB, a well-described mechanism termed Trojan horse.
Although experimental evidence regarding SARS-CoV-2 neuroinvasiveness is still lacking, post-mortem studies have shown the virus’s presence in the brain microvasculature, cerebrospinal fluid, and even neurons. Studies have also demonstrated that the ACE-2 receptor is expressed on neuron and glial cells of structures such as the olfactory epithelium, cortex, striatum, substantia nigra, and the brain stem¹⁷, thus supporting the SARS-CoV-2 potential to infect cells throughout the CNS.
So what is happening to our brains?
First off, a few facts. It is unclear if the neurological symptoms of COVID-19 result from cytokine storm-induced neuroinflammation or the infection of some brain areas. Irrespective, the CNS and immune system involvement might have remarkably neurologic long-term consequences, including the development of neuropsychiatric disorders. Expanding the research and science in this area is key to furthering our understanding.
Neurological Manifestation of COVID-19, short and long-term
It‘s been widely described that a broad spectrum of virus infection can spread through the body and eventually reach and affect the mammalian peripheral nervous system (PNS) and CNS when optimal conditions exist. For instance, the hypoxia promoted by respiratory distress has been associated with disturbed brain metabolism and a subsequent neurological manifestation¹⁸.
Evidence appears to support the neuroinvasive and neurotropism and possible long-term neurological sequelae of coronaviruses, including SARS-CoV and MERS-CoV¹⁹.
Emergent data from case reports and clinical studies demonstrate that covid patients exhibit some CNS and PNS complications, ranging from mild to fatal. The most frequent neurological symptoms are mostly nonspecific in the short term, such as loss of smell and taste, headache, malaise, myalgias, and dizziness. In contrast, moderate-to-severe cases developed acute cerebrovascular diseases, impaired consciousness, and skeletal muscle injury²⁰. These manifestations can be considered a direct virus effect in the CNS.
Unfortunately, your recovery from an acute infection does not promise a full viral clearance, and if the infection becomes chronic, it may result in long-term sequelae(an aftereffect of a disease), including chronic neurological impairment¹⁸. Some studies report the coronavirus persistence in the CNS and some neurologic and tissular affections¹⁹.
In mice surviving acute encephalitis caused by OC43-CoV, the viral RNA could be detected even six months post-infection; in correlation with the viral persistence, these mice also display a reduced locomotor activity, subjacent decreased density of hippocampal layers, and gliosis.
The RNA of MHV-CoV is detectable in the brain, even 10–12-month post-infection. Chronic-CNS demyelination persists as late as 90 days post-infection to scattered demyelinated axons at 16 months after infection²¹. Case reports support that neurotropic viral infection promotes an exacerbated inflammatory response leading to encephalitis or CNS-target autoimmune (i.e., demyelination) response in COVID-19 patients.
Guillain-Barre and Miller-Fisher cases are reported without SARS-CoV-2 detection in cerebrospinal samples, supporting the inflammatory response’s role in neurological manifestations.
Whether the dysregulated immune response remains after the illness resolves, neurological disorders can be developed, including dementia, depression, and anxiety. Additionally, hypoxia and cerebrovascular diseases reported in COVID-19 patients, particularly encephalitis and stroke, are expected to produce permanent or at least long-term neurological impairments for affected patients.
A cohort study reported an altered mental status, reflecting neurological and psychiatric, such as encephalopathy, encephalitis, psychosis, and dementia-like syndrome in patients from 23–94 years old; however, cerebrovascular events predominated in older patients²². Additional neurological complications reported in other coronaviruses infections may also be applicable for SARS-CoV-2 and further research is needed.
Fixating on issues such as locating the source or natural reservoir for the original point of infection for the SARS-CoV2 virus is, at this stage, premature and a waste of precious resources. It may be worthwhile pointing out that we have still not located the origins of the Ebola virus and for both viruses, never may. Clearly, our attention needs to be focused on developing a deeper and clearer understanding of covid’s mechanisms to fully address the pathological consequences for our bodies, some of which are only now becoming apparent, and no doubt, more will emerge over time.
Unless we want covid’s lasting legacy to be one of chronic illness affecting millions, we know where we need to be focusing our attention, and that focus needs to be immediate.
Acknowledgements
The following paper, entitled ‘Infection Mechanism of SARS-COV-2 and Its Implication on the Nervous System’ was broadly referenced in this article. To view the original, please follow the link.
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