About 50% of people confirmed to have COVID-19 report a loss or reduced sense of smell. But does this imply that the virus is neuro-invasive via olfactory neurons? A new study concludes that the olfactory nerve is an unlikely route to brain infection, which is considered a rare occurrence in humans.
Almost half of those confirmed to have been infected with the novel coronavirus have reported loss of smell (Jian Fan / Getty Images / iStock)
Loss of smell = brain infection? Not so fast …
It is now well established that one of the most common symptoms of COVID-19 is loss of smell. When the new coronavirus infects the nasal epithelium, does that mean the virus can travel along the olfactory nerve to the brain? Recent publications give the impression that this has been proven: “Transmucosal olfactory invasion of SARS-CoV-2 as a central nervous system entry port in people with COVID-19“and”The olfactory pathway is a potential way for SARS-CoV-2 to invade the central nervous system in rhesus monkeys”. Such publications and the attention they garner in the media are grounds enough to instill fear in COVID-19 patients who have lost their sense of smell. If the virus has altered their sense of smell, does that mean that the virus is also present in their brain – it is just waiting to cause brain fog, spread throughout the brain and kill the patient or, s does he recover, greatly increasing his chances of developing neurodegenerative disease?
Olfaction, a gateway to brain infection?
Our team of investigators from Poland, France and the USA examined the evidence that the new coronavirus infects olfactory neurons and travels along olfactory nerve axons from the nose to the brain. There is a broad consensus on the absence of the obligatory entry proteins of the virus in the olfactory receptor neurons. Such input proteins are expressed abundantly in the support cells, which become infected and die, reduce function adjacent olfactory receptor neurons. It is commonly thought to cause loss of smell in COVID-19. In a few days, the support cells regenerate, the neurons resume their function and the smell returns in most patients within 1-2 weeks. The discovery of the new coronavirus in olfactory nerve axons is extremely rare, making it an ineffective route to brain infection.
The evidence just doesn’t add up
So why do many reports advocate an olfactory pathway to brain infection? One of the reasons is that neurons and their supporting cells are closely related and can easily be confused on confocal microscopy. Another reason is that the virus can indeed reach the brain, especially in genetically modified mice where the virus input proteins are abnormally expressed. But careful analysis shows that the time course and route of virus progression in animal models is incompatible with a transfer of olfactory neurons from the nose to second and third order neurons in the brain. Instead, the data shows a rare but fulminating appearance of the virus in the brain – suggesting a route through blood vessels, cerebrospinal fluid, or traveling along a shortened nerve fibers that bypass the olfactory bulb and project directly onto targets in the forebrain. We are fortunate that the lack of virus entry proteins into olfactory neurons creates an effective barrier that prevents olfactory infection in the brain.
Does the virus replicate in the brain?
It should be noted that unlike some animal models, the virus is rarely found in the human brain. In addition, many studies have relied on methods that do not prove that a virus replicates, but instead detects virus RNA or viral proteins that can be excreted and circulate systematically, without providing conclusive evidence of brain infection. The significance of the viral presence in the brain is not yet clear. Some researchers believe that infection of the brainstem and respiratory centers may contribute to fatal outcomes from COVID-19, while others note that there is no correlation between evidence of viruses in the brain or cerebrospinal fluid and the severity of COVID-19.
COVID patients who have lost their sense of smell may breathe a sigh of relief. Just because their supporting cells in the nose got infected doesn’t mean the virus found an easy path from the nose to the brain. Our analysis current evidence indicates that the vast majority of COVID-19 patients will not have a brain infection, even if they temporarily lose their sense of smell.
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