Infection | Brain
4 Clues That SARS-CoV-2 Invades the Brain
[updated 26/3/20] “They’re just not thinking that the brain could be the site of the problem,” says a neuropathologist.
First appearing in Wuhan, China in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — that causes COVID-19 — is now a pandemic. As the name implies, SARS-CoV-2 is characterized as a lethal respiratory infection.
But “increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases,” Dr. Tsutomu Hashikawa from Riken Brain Science Institute, Japan, and his colleagues Dr. Yan‐Chao Li and Dr. Wan‐Zhu Bai from China, wrote in a 2020 review published in Medical Virology.
The paper was titled “The neuroinvasive potential of SARS‐CoV2 may be at least partially responsible for the respiratory failure of COVID‐19 patients.” And it hints at 4 reasons why SARS-CoV-2 can invade the nervous system or, more specifically, the brain.
Hint 1: Evolutionary Relatedness
Bioinformatics analyses show that SARS-Cov-2 belongs to the same evolutionary clade — βCoV — as SARS-CoV and MERS-CoV.
Evolutionarily-related microbes — or any organisms for that matter — always bear functional similarities. To illustrate, they are all lethal respiratory diseases that show similar clinical symptoms and mechanisms of infection — such as neuroinvasiveness.
Indeed, all previous types of coronaviruses — SARS‐CoV, MERS‐CoV, HCoV‐229E, HCoV‐OC43, mouse hepatitis virus, and porcine hemagglutinating encephalomyelitis coronavirus (HEV) — are known to be neuroinvasive.
So, chances are that SARS-CoV-2 can invade neurons as well.
Hint 2: Receptor Distribution
To infect a cell, the virus must first attach to a receptor on that cell surface. This is a basic requirement for all viruses; no exceptions exist as of now. Curious about why our cells have receptors for the entry of viruses?
Why Do Our Cells Have Receptors For Viruses?
It’s the reverse: Viruses evolve to fit our cell receptors.
SARS‐CoV-2 enters the host cell via a receptor called angiotensin-converting enzyme 2 (ACE2) — exactly like SARS-CoV. Obviously, ACE2 is expressed on the cell surface of the human respiratory tract. But ACE2 is also present in the brain at lower levels.
It should be noted that the presence of receptors doesn’t confirm an infection. The small intestinal cells, for instance, do have ACE2 receptors on their surface but SARS-CoV doesn’t infect them. Why? Nobody knows for sure; maybe the virus may not even travel that far or it can’t survive in the acidic conditions therein [thanks to Lanu Pitan who suggests the latter example].
How did SARS-CoV enter their brains? A receptor must be involved as it’s a prerequisite for all viruses. And that receptor is most likely ACE2 — as it’s known to be expressed in the brain — that enables the entry of both SARS-CoV and SARS-CoV-2. Chances are that SARS-CoV-2 behave like SARS-CoV and might already be present in the brains of infected people.
Another 2020 review published in ACS Chemical Neuroscience written by a group of Pakistanian researchers — titled “Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms” — also emphasized on the significance of ACE2 receptors in the brain as a means for SARS-CoV-2 to establish a brain infection.
“In light of the high similarity between SARS‐CoV and SARS‐CoV-2, it is quite likely that SARS‐CoV‐2 also possesses a similar potential,” agreed the authors, Li and colleagues, of the other 2020 review in Medical Virology.
Hint 3: Animal Studies
In transgenic mice that have the ACE2 gene in their genome, inoculating SARS-CoV into their nose resulted in brain infection. The virus first spreads to the olfactory bulb — presumably via the olfactory nerves — and then reaches other brain areas such as the thalamus, cerebrum, and brainstem.
And other coronaviruses have also been found to invade the host brain:
- MERS-CoV infected the lungs and brain — particularly the thalamus and brainstem — of transgenic mice when the virus was inhaled.
- HEV 67N, another type of coronavirus, was found to invade the pig’s lungs, intestines, and brain — involving the cerebellum, cerebrum, and brainstem — via the nose and mouth.
- Avian coronavirus, when inhaled by mice, infected the vagus nerve, brainstem, and lungs.
It’s not a coincidence why the brainstem is targeted. The brainstem harbours the nucleus of the solitary tract that receives sensory information from the lungs and respiratory tracts. This nucleus also sends neuronal information to the smooth muscles, glands and blood vessels in the respiratory tract.
“Such neuroanatomic interconnections indicate that the death of infected animals or patients may be due to the dysfunction of the cardiorespiratory centre in the brainstem,” Li et al. said.
“The possible neuroinvasion of SARS‐CoV‐2 may also partially explain why some patients developed respiratory failure, while others not,” they continued.
And based on data on the latency time of SARS-CoV-2, it’s “enough for the virus to enter and destroy the medullary [part of the brainstem] neurons,” the authors said. “As a matter of fact, it has been reported that some patients infected with SARS‐CoV‐2 did show neurologic signs, such as headache (about 8%), nausea, and vomiting (1%).”
Hint 4: Loss of Smell [26/3/2020 update]
Throughout the world, many patients suffering from COVID-19 had reported a loss of sense of smell, that is, anosmia — as Robert Roy Britt has written in Elemental. This can either be a symptom of inflamed nasal lining or neurological damage of the olfactory system.
A Lost Sense of Smell: All About the Strangest New Coronavirus Symptom
Loss of smell appears to be yet another symptom to watch for in people who otherwise are not extremely ill
The possibility of the latter “is something to keep a careful eye on,” the neuropathologist, Professor Matthew Anderson at Beth Israel Deaconess Medical Center, Boston opined. “There’s been some intriguing observations in previous studies on viruses, including coronaviruses, to show that they have the capacity to enter the nervous system.”
Further, the proposition that SARS-CoV-2 cause neurological damage to the olfactory system is consistent with how other known coronaviruses infect the brain via olfactory neurons (as discussed above).
The olfactory neurons are “connected to the olfactory bulb, via small, sieve-like, tiny openings called the cribriform plate that is located at the base of the frontal lobes of the brain,” says the senior Pakistanian researcher, Abdul Mannan Baig at Aga Khan University. This direct neuronal connection of the olfactory system bypasses the blood-brain-barrier.
What it means for us now [also see author’s note below]
 If SARS-CoV-2 does infect the brain, then antiviral treatment targeting the airways should be made urgent to inhibit virus replication before it spreads to the brain during its latency period, Li and colleagues recommended.
 If SARS-CoV-2 spreads to the brain via the nose, like SARS-CoV, then face mask or any nasal protection for that matter, is more crucial than ever, they emphasized.
 If SARS-CoV-2 behaves like a typical brain virus in its ability to lie dormant in the neuronal genome, then it likely stays for life with the possibility of reactivation in the future under conditions of immunosuppression and cellular stress. “Since SARS‐CoV-2 may conceal itself in the neurons from the immune recognition, complete clearance of the virus may not be guaranteed even the patients have recovered from the acute infection,” Li et al. explained.
“Therefore, given the probable neuroinvasion, the risk of SARS‐CoV‐2 infection may be currently underestimated.”
 “It is important to screen the patients for neurological signs early and late in the course of COVID-19,” Manna remarks, “as this could be life-saving in our fight against COVID-19 pandemic.” Autopsies should also be conducted to examine any signs of brain damage of COVID-19 victims. But autopsies to date only look at the lungs and not the brain.
“They’re just not thinking that the brain could be the site of the problem,” asserts Professor Anderson.
And Professor Anderson was right. There’s a new case of Covid-19 encephalitis (i.e., brain inflammation) with SARS-CoV-2 being identified as the causative agent. In brief, researchers have detected the presence of SARS-CoV-2 genes in the cerebrospinal fluid of a Covid-19 patient. This shows, for the first time, that SARS-CoV-2 has directly attacked the brain.
First Case of Covid-19 Encephalitis
New evidence that SARS-CoV-2 infiltrates the brain (and its ramifications)
Thanks to a kind email, it seems that the online Li et al. paper stated that “Correction added on March 17, 2020, after first online publication: Manuscript has been revised with author’s latest changes.”
Upon reading the online full text again, they deleted an entire section called “The implications of the potential neuroinvasion of SARS-CoV-2” from which the first three abovementioned points were derived. Perhaps the authors were criticized for suggesting precautions based on theoretical evidence.
I have the original full-text pdf saved. Any interested reader please feel free to email me. And thanks to those who have done so :)