Smell Loss Could Be A Neuroprotective Mechanism Against Covid-19

The ability of olfactory neurons to self-renew may be an evolutionary adaptation to environmental threats.

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A meta-analysis pooling data from 10,818 Covid-19 patients calculated the prevalence of anosmia (loss of smell) and ageusia (loss of taste) to be at 74.8% and 81.6%, respectively. Smell and taste strongly associate with people who can’t smell often can’t taste as well.

In one European cohort study, they found 79.9% of Covid-19 patients with an impaired sense of smell did not have nasal obstruction or rhinorrhea. Thus, a stuffy or runny nose brought about by inflammation is not the reason for the olfaction disturbance in Covid-19.

Scientists, therefore, believe that the plausible reason is that something went wrong with the olfactory nervous system. “This killing of the olfactory nerve cells is likely to be the main reason people lose their sense of smell after an infection,” The Conversation reported. “Once 20–30% of the olfactory nerve cells have died, people will report they have lost their sense of smell.”

Naked Olfactory Neurons

Odor molecules entering the nostrils bind to olfactory receptor neurons, which send signals directly to the olfactory bulb and cortex. In this way, the olfactory neurons bypass the blood-brain barrier and are nakedly exposed to the outside world.

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The advantage is that it provides a rapid sense of environmental chemicals, such as food or smoke, which are critical for survival, especially in animals that rely heavily on smell.

The downside is microscopic pathogens capable of invading the brain usually exploit this olfactory pathway. “Viruses that can use the olfactory nerve as a shortcut into the [brain] include influenza A virus, herpesviruses, poliovirus…,” a 2015 review in the Journal of Pathology stated.

Coronavirus and Olfactory Nervous System

Science has previously shown, in a mice model, that SARS-CoV can spread from the nose to olfactory neurons to the olfactory bulb and other brain areas including the cardiorespiratory center, brainstem. Similarly, intranasal infection of SARS-CoV-2 into mice led to high virus replication in the lungs and brain, but the study did not examine if olfactory nerves are involved.

But in a July study with hamsters, scientists confirmed that SARS-CoV-2 infected the olfactory epithelium and neurons — causing inflammation and neuronal death. As the authors concluded: “SARS-CoV-2 productively infected olfactory neurons…of hamsters and induced apoptosis. In addition, SARS-CoV-2 also infected sustentacular cells and submucosal glands that might adversely impact the viability and function of olfactory neurons.”

Autopsy and brain imaging studies support the olfactory neuroinvasion of SARS-CoV-2.

An autopsy has uncovered nerve damage and virus particles concentrated along the olfactory neurons and brainstem of a Covid-19 patient that died of respiratory failure. In a brain magnetic resonance imaging (MRI) study of a healthy 25-year-old woman with Covid-19-related loss of smell and taste, the olfactory bulb displayed hyperintensity on the 4th day of symptoms onset. After 28 days, the olfactory bulb hyperintensity reduced and she regained smell and taste function. MRI hyperintensity reflects neuronal damage or loss. Another brain MRI study, published in June, also found olfactory bulb injury in five Covid-19 patients. And, lastly, a Lancet study confirmed that SARS-CoV-2 replicates in neuronal cell lines. More details on the link between the olfactory nervous system, brainstem, and Covid-19 are detailed here.

The Neuroprotective Hypothesis

In a paper, “Is anosmia the price to pay in an immune-induced scorched-earth policy against COVID-19?,” otorhinolaryngology researchers at St. Peter’s Hospital in Belgium pondered: “Could it be that some people lose smell, not because the [Covid-19] virus destroyed olfactory neurons but because our body evolved to bomb the bridge in a scorched-earth strategy?”

This concept is credited to Isamu Mori, a Japanese researcher specializing in neuroinvasive viruses, who proposed, based on a series of experiments, that the early death of olfactory neurons rescued animals from viruses attacking the brain. In an example of mouse hepatitis coronavirus, surgical removal of the olfactory bulb halted the coronavirus spread from olfactory neurons into the brain.

“Of importance, death of olfactory receptor neurons is compensated by the self-renewal mechanism,” Mori wrote. This feature is unique as most types of neurons do not actively regenerate. But olfactory neurons undergo apoptosis and regrowth from the olfactory bulb every 30 to 120 days. By analogy, the disrupted smell in Covid-19 may take up to 120 days to recover, which is consistent with the current situation — that smell loss usually lasts for a few weeks or months.

Evolution may have endowed olfactory neurons the ability to readily self-destruct and regenerate to compensate for their naked exposure to the outside world.

In the current pandemic, the impaired sense of smell without any runny or stuffy nose implies that olfactory neurons are either malfunctioning or dead. The autopsy study mentioned above suggests the latter. But either way, viruses would not be able to hijack olfactory neurons for their replication and spread into the brain.

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Evidence for the Hypothesis

Science agrees that impaired smell is one of the earliest signs of Covid-19; about 75% of infected people experienced it. Yet the CDC reports that the cumulative hospitalization rate of Covid-19 is 7.3 per 100,000 people. This wide gap in prevalence shows that the majority of people having disrupted sense of smell did not progress into severe Covid-19, probably owing to the neuroprotective mechanism at play.

“Normosmia is an independent predictor of admission in Covid‐19 cases,” concludes a California study of 169 patients. “Smell loss in Covid‐19 may associate with a milder clinical course.” Normosmia means normal olfactory function. Similarly, a Spain study published in June found those experiencing smell loss early had a 58% lower odds of progressing into severe Covid-19. Moreover, a China study reported that only 5.1% of 214 hospitalized patients had smell disturbance. This is rather a huge gap compared to the usual prevalence of smell loss of roughly 75%.

These studies indicate that a disrupted sense of smell may be a sign of a good prognosis for Covid-19. Not to mention that the hamster, autopsy, and MRI findings discussed above also support the olfactory neuroinvasion of SARS-CoV-2.

“We posit that COVID-19-related anosmia may be the consequence of a programmed immune-mediated self-defense mechanism by olfactory nerve deafferentation, as it is a known royal path to the brain,” the 2020 review by otorhinolaryngology researchers wrote. “Besides, such a drastic protective strategy is all the more worth the risk since the olfactory nerve has the rare ability to regenerate.”

This article was originally published in Microbial Instincts with minor modifications.

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