Why do people lose their sense of smell after COVID-19?The latest Cell paper finally figured it out!

2022-06-17 0 By

A loss of the sense of smell is one of the most common symptoms of COVID-19, but the mechanism behind this has not been clarified.The novel Coronavirus study, published in the journal Cell, has finally revealed that the novel Coronavirus causes downregulation of the olfactory receptors, preventing the normal detection of odor-related molecules.A press release accompanying the paper notes that coVID anosmia is a very unique phenomenon because similar symptoms are not observed in the common cold, and anosmia is not associated with nasal congestion.In most cases, the loss of smell caused by COVID-19 lasts for a few weeks, but more than 12 percent of infected people experience long-term symptoms, including persistent anosmia, or changes in smell — how the same smell is perceived differently before and after COVID-19.To understand the reasons behind this, the scientists decided to use hamster and human olfactory epithelium as models to study the effects of novel coronavirus infection.In hamster models, the researchers used single-cell sequencing to study changes in gene expression within 10 days of infection.A decline in the sustentacular cell (ACULAR cell) was detected one day after infection and intensified by day 3 after infection.In response, levels of immune cells such as microglia rose.Both returned to their pre-infection levels ten days after infection.Meanwhile, levels of olfactory sensory neurons (OSNs) in hamsters remained stable during the infection without significant fluctuations.This result indicates that the pillar cells may be the primary target of novel Coronavirus infection and is consistent with another paper published in Cell in 2021.In addition, the researchers found that one day after infection, 47 percent of the cells infected with the virus were pillar cells.By contrast, only 6 percent of the infected cells were olfactory sensory neurons.Because novel Coronavirus does not infect olfactory sense neurons very much, researchers suspect that novel Coronavirus affects olfactory sense not by killing these neurons, but by disrupting gene expression in them, thereby affecting their function.Follow-up studies confirmed this: three days after infection, these neurons activated an antiviral response.Some genes critical to olfaction, such as Adcy3, were significantly downregulated three days after infection.Biochemical experiments also confirmed that the mRNA and protein levels of Adcy3 were significantly decreased in the olfactory epithelium of these hamsters.What’s more, this is true even in areas where the virus has barely been detected!To more fully understand the changes in gene expression, the researchers sequenced RNA from these samples and found that two days after infection, the neuronal progenitor cells had down-regulated expression levels of several transcription factors associated with olfactory receptors and olfactory receptor signaling pathways.Ten days after infection, even after levels of other markers associated with olfactory sensory neurons had returned to normal, the genes involved in these olfactory receptors were still abnormally downregulated.The researchers then further explored the mechanism by which these olfactory receptors are downregulated.They show that olfactory receptor expression is regulated by the OSN nuclear architecture, in which clusters of olfactory receptor genes on different chromosomes are clustered together in a region that allows olfactory receptor genes to be transcribed steadily.Now that the expression levels of these genes are significantly down-regulated, could it be that something is wrong with these nuclear structures?Sure enough, one day after novel coronavirus infection, contact between different chromosomes has decreased.The effect peaked on the third day.This effect did not disappear with subsequent virus clearance.In contrast, at ten days of infection, when the Novel Coronavirus is no longer present in the olfactory epithelium, these regions, which are important for gene expression, remain out of order.Subsequent studies have found that novel Coronavirus immune responses may also be contributing — serum from hamsters three days after infection (with the strongest immune response) can still induce downregulation of olfactory receptors even after viral destruction.This phenomenon is not unique to hamsters.Using human olfactory epithelial samples taken at autopsy, the researchers also found that COVID-19 infection caused downregulation of olfactory receptor genes, as well as genes associated with signaling pathways.And in human samples, they also observed that olfactory gene regions from different chromosomes failed to form the proper internal structure to produce olfactory receptors.Taken together, the studies indicate that in novel coronavirus infection, the expression of olfactory receptor-related genes is disrupted for a long time.This may be why, even after the Novel Coronavirus has been cleared of the human body, people still suffer the side effect of losing their sense of smell for a long time.”Recognizing that smell depends on fragile binding relationships between chromosomes has very important implications,”Professor Benjamin R. tenOever, one of the study’s corresponding authors, said, “If the expression of olfactory genes were shut down every time the immune system made a specific response that interfered with the contact between chromosomes, the loss of smell could be the ‘canary in the coal mine’, providing an early signal before other symptoms developed.It shows that Novel Coronavirus is damaging brain tissue.”The authors also point out that olfactory neurons are linked to sensitive brain areas, so some immune responses may affect mood and thinking.That may explain why some people suffer long-term aftereffects after recovering from COVID-19.