In the early days of the coronavirus pandemic, a curious symptom reported by experts and patients alike was identified as more than enough reason to get a COVID test: loss of smell. In trying to understand exactly how the sense of smell is lost, a recent study reports two important discoveries. First, there is no evidence that the olfactory system allows the virus to enter the brain, and second, a major role is played by little-known cells in the olfactory system that have barely been examined in humans.
Scientists had until now been concerned with the question of whether neurons (or nerve cells) in the olfactory system – which are among the most exposed neurons in the nervous system – provide the coronavirus with a pathway to the brain. That would make the coronavirus a neurotropic virus – a virus capable of infecting nerve cells – like herpes, polio, rabies and others. But according to the researchers, who published their findings in the journal Cell, there is no evidence that the virus infects olfactory neurons. Instead, they found that the virus targets sustentacular (or supporting) cells in the olfactory mucosa in the nose.
It was only after the outbreak of the coronavirus that scientists began to take an in-depth look at the role of these cells; until the current study, sustentacular cells were only examined in laboratory animals such as mice and rats. According to lead researcher Peter Mombaerts of the Max Planck Research Unit for Neurogenetics in Frankfurt, Germany, scientists have yet to understand the role of these cells in humans.
Mombaerts says that, to put it simply, according to scientific literature, these cells provide structural and metabolic support. “I have been working in the field of olfactory research for 28 years and we have completely neglected sustentacular cells. We just focused on neurons, even though there is roughly one sustentacular cell for each neuron.”
Mombaerts reviewed all the research literature and found just one study, from 1990, in which the morphology of these cells in humans had been described. A handful of other studies dealt with sustentacular cells in laboratory animals. “These cells are the unsung heroes of the olfactory system, and now they have become very important,” he says.
Sustentacular cells are particularly elusive; they are located in the upper layer of the olfactory mucosa, hidden deep in the nasal cavity. A biopsy can only be taken with the patient under general anesthesia, says Mombaerts, but even under these conditions, they can’t always be located unambiguously. “This tissue is very close to the brain, and even the smallest miss could be problematic,” he explains. “The risk to the COVID patients is very high.”
This makes getting tissue from living COVID patients extremely difficult, so the researchers collected samples from patients who had recently died of COVID. An ear-nose-and-throat team from the University Hospitals Leuven in Belgium and a large hospital in Bruges, Belgium developed a special surgical protocol to take tissue samples at the bed of the patient within 90 minutes of death. The short timeframe enabled the researchers to analyze the tissue samples using biomolecular techniques. The control group constituted of tissue samples taken from patients who had died of other causes and were not infected with the coronavirus at the time of their death.
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Mombaerts’ lead partner in the study was Dr. Laura Van Gerven, an ENT surgeon at the University Hospitals Leuven. She could not join them on the call, he said, as all non-urgent surgeries had been suspended in Belgium as of last week. “The wards are full of COVID patients. She is trying to get as many surgeries as possible done now,” Mombaerts said.
The samples collected in Belgium were sent to Frankfurt, where a team led by Dr. Mona Khan examined them using an ultrasensitive technique known as RNAscope. This method enabled the researchers to identify various types of viral RNA molecules within single cells. Mombaerts and colleagues found that the virus infected sustentacular cells in the olfactory epithelium and replicated within them vigorously, and that the virus did not infect nearby nerve cells.
In order to infect a cell, the virus has to bind to a receptor on the cell membrane. Typically, it binds using the ACE2 receptor. ACE2 is present on the surface of sustentacular cells, but not on olfactory system neurons, consistent with the findings of this study.
Prof. Masha Niv, of the Department of Biochemistry, Food Science and Nutrition at Hebrew University, calls the research “encouraging.” “It now seems that the coronavirus doesn’t directly harm neurons, but rather the cells that support them,” she says. “It turns out that these cells, which do their job behind the scenes, play a very significant role, because when they are harmed our sense of smell doesn’t work. This wasn’t known until recently, because until the current pandemic, we hadn’t seen a massive and dramatic impact on our sense of smell.”
Niv adds that it will be interesting to see whether there is a similar system of support cells located close to taste cells, because coronavirus infection can also affect the sense of taste. She notes that the fact that the study found no signs that neurons were infected with the virus does not rule out the possibility that such infection is possible, as the researchers noted in their paper.
A study conducted by Niv and her partners, published last year in Open Forum Infectious Diseases, found that 70 percent of patients infected with early variants of the virus reported a strong and sudden decline in their sense of smell. Niv says that now they can infer that their sustentacular cells had suffered damage.
Even patients who experienced no change in sense of smell contracted the virus via the nasal passage, which Niv says is very significant. “One can assume that researching these cells will give us a better understanding of the differences [patients experience] in the course of the illness, and will perhaps advance new solutions for preventing infection, or at least alleviating symptoms,” Niv says.
Mombaerts says that the sustentacular cells are located near the surface of the olfactory mucosa, an exposed area with no blood vessels. This makes it difficult for the immune system to protect them. It is likely, then, that the olfactory system is at risk of coronavirus infection and malfunctioning in the vaccinated and unvaccinated alike, he adds.
COVID, he notes, can cause two serious disorders – anosmia, complete or partial loss of smell; and parosmia, a change in the perception of odors. People suffering from parosmia, Mombaerts explains, suddenly find the smell of meat or coffee to be terribly noxious. “It has a severe effect on nutrition and is perhaps worse than anosmia. It may occur due to the infection of sustentacular cells, and we want to better understand how it happens.”
The new study, enlightening though it is, is limited, Mombaerts notes, as they could not take tissue samples from living patients.
“It is an important lesson in the financing of research,” he says. “We need research that is not targeted at a particular purpose – research that has been conducted purely out of curiosity, even if it deals with esoteric matters. If we don’t have this kind of research, something like the current pandemic happens, and you don’t know what do to. If we had known more about supporting cells, we would have known how to protect them. But we don’t know a thing. It’s quite incredible.”