Temporary loss of smell is one of the hallmark symptoms of COVID-19. But how does the coronavirus do it? According to a recent study, infected non-neuronal support cells is likely the cause.
The association between infected support cells and loss of smell was unveiled by an international team of scientists, led by Harvard Medical School (HMS), the graduate medical school of Harvard University. Their findings suggested cells that support the olfactory function could be more vulnerable to the coronavirus, compared to olfactory sensory cells. They found these support cells with significant ACE2 expression than olfactory cells. Once infected, the cells would impair the correct function of the sense of smell. They published their findings in the journal Science Advances.
The Loss of Smell Due to COVID-19
A few months after the first outbreak of COVID-19 in China, clinicians found peculiar symptoms experienced by some patients. One of these odd symptoms has been the loss of smell that indicated an olfactory dysfunction. While such dysfunction is normal in most respiratory diseases, a sufferer often experiences a stuffed nose that causes the temporary loss of smell or anosmia. In COVID-19, a stuffed nose is not a common, less common, or serious symptom. The symptom is usually linked to the common cold or influenza, with higher frequency in the former.
In a meta-analysis submitted on April 24, 2020, in the American Academy of Otolaryngology – Head and Neck Surgery, lead author Jane Y. Tong found loss of smell and loss of taste were prevalent among COVID-19 patients. Out of reviewed literature up to April 2020, authors identified the prevalence rate of those dysfunctions based on submitted reports. A total of 10 studies yielded 1,627 COVID-19 cases, and out of those, 52.73% were confirmed with anosmia. A total of nine studies yielded 1,390 COVID-19 cases, and out of those, 43.93% were confirmed with dysgeusia or loss of taste.
In the loss of smell analysis, 845 patients reported some level of olfactory dysfunction. Quantitatively, the prevalence of the dysfunction was between 5.14% and 98.33%, which yielded the 52.73% rate using a random-effects model. In the loss of taste analysis, 626 patients reported some level of gustatory dysfunction. The prevalence of the problem was between 5.61% and 92.65%, which yielded 43.65% using the same model.
The analysis of non-validated survey measures showed a 36.64% prevalence rate of anosmia in 913 patients. While analysis of the similar non-validated survey measures for dysgeusia revealed a prevalence of 86.60% in 714 patients. The authors concluded that the loss of smell and taste are common COVID-19 symptoms. Awareness of these symptoms could increase early diagnosis and treatment of the disease.
How SARS-CoV-2 Affects the Sense of Smell
A Harvard-led international team of neuroscientists investigated how the novel coronavirus influences a person's sense of smell. They examined what cells associated with olfactory function could be infected. They found that cells mainly responsible for smell are not susceptible to the virus. But cells supporting the sensory cells were prone to the pathogen.
"Our findings indicate that the novel coronavirus changes the sense of smell in patients not by directly infecting neurons but by affecting the function of supporting cells," said Sandeep Robert Datta, the senior author of the study and associate professor of neurobiology in the Blavatnik Institute at HMS.
Neuroscientists analyzed existing single-cell sequencing datasets that cataloged numerous cells found in the upper cavities of humans, non-human primates, and mice. They searched for cells that express the gene for ACE2 receptor protein – the component SARS-CoV-2 needs to infect host cells. The greater the expression was, the better it would be for the virus. Thus, cells with very low expression levels would unlikely to be infected.
Furthermore, they searched for another gene called TMPRSS2 that encodes an enzyme linked to SARS-CoV-2 cellular entry. Then, they compared the expression levels of the two genes in cells. Results showed that both ACE2 and TMPRSS2 were expressed by cells in the olfactory epithelium, a tissue in the roof of the nasal cavity. Olfactory epithelium specializes in odor detection since it houses both olfactory sensory neurons and select supporting cells.
When scientists looked into both cells in the said tissue, they were surprised that the olfactory sensory neurons lacked the expression of both genes. That means the neurons could not be infected by SARS-CoV-2. However, the neurons were detected expressing genes other coronaviruses could use to infect them. On the other hand, supporting cells expressed the genes that made them prone to SARS-CoV-2.
Two supporting cell types in the tissue had expression levels of ACE2 similar to the observed cells in the lower respiratory tract. These were basal and sustentacular cells. Basal cells act as stem cells to regenerate the tissue for damage repairs. While sustentacular cells wrap the sensory neurons and provide assistance in metabolism and structure. The expression levels of ACE2 and TMPRSS2 in those cells were confirmed via immunostaining.
Additional experiments were performed in olfactory epithelium stem cells. Experiments showed that when artificially damaged, the cells would express ACE2 at higher levels than those in a resting state. That suggested a higher vulnerability to SARS-CoV-2, but not enough to define importance in the clinical course of anosmia.
In mice, scientists analyzed almost 50,000 individual cells in the olfactory bulb of the animals. They examined the gene expression of these cells. Neurons in the mouse olfactory bulb showed no expression of ACE2. Yet the gene and its related protein were traced in pericytes – cells in the blood vessels responsible for blood pressure regulation, inflammatory responses, and blood-brain barrier maintenance. No other cells in the studied area showed an ACE2 expression.
Scientists concluded that anosmia experienced by some COVID-19 patients could be correlated to the supporting cells in the olfactory epithelium. As SARS-CoV-2 infects those cells, changes would indirectly influence sensory cells responsible for the sense of smell. Although most COVID-19 cases with anosmia do not lead to permanent olfactory damage, there might be a lasting effect in some survivors. The lasting effect could be a psychological consequence.
The team said that sustentacular cells have been largely ignored for some time. But with the prevalence of olfactory dysfunction in COVID-19, researchers may take them seriously and potentially unravel more secrets of SARS-CoV-2.