They discover the mechanism that causes loss of smell due to COVID-19


Researchers have discovered a mechanism that could explain why COVID-19 patients lose their sense of smell.

Published online in the journal Cell, the new study finds that infection indirectly reduces the action of olfactory receptors (OR), proteins located on the surface of nerve cells in the nose that detect molecules associated with odours. .

Led by researchers at New York University Grossman School of Medicine and Columbia University, the new study may also shed light on the effects of COVID-19 on other types of brain cells and on other effects persistent neurological symptoms of COVID-19 such as “brain fog,” headaches, and depression.

The experiments showed that the presence of the virus near nerve cells (neurons) in the olfactory tissue triggered a surge of immune cells, microglia and T cells, which detect and counter infection.

These cells release proteins called cytokines that modify the genetic activity of olfactory nerve cells, even though the virus cannot infect them, the study authors say.

While immune cell activity would dissipate rapidly in other scenarios, in the brain, the team theorizes, immune signaling persists in a way that reduces the activity of genes needed to build olfactory receptors.

“Our findings provide the first mechanistic explanation for smell loss in COVID-19 and how this may underlie the long-standing biology of COVID-19,” said co-author Benjamin tenOever, a professor in the Department of Microbiology at NYU Langone Health. The work, added to another study by tenOever’s group, also suggests how the pandemic virus, which infects less than 1% of cells in the human body, can cause such severe damage to so many organs.”

According to the researchers, a unique symptom of COVID-19 infection is loss of smell without the nasal congestion seen in other infections such as the common cold.

In most cases, the loss of smell lasts only a few weeks, but in more than 12 percent of COVID-19 patients, olfactory dysfunction persists in the form of continued reduction in the ability to smell (hyposmia) or changes in the way the person perceives the same odor (parosmia).

To better understand COVID-19-induced loss of smell, the current authors explored the molecular consequences of SARS-CoV-2 infection in golden hamsters and in olfactory tissue taken from 23 human autopsies. Hamsters represent a good model, as they are mammals that rely more on the sense of smell than humans and are more susceptible to nasal passage infection.

The study results build on the discovery, made over many years, that the process that turns genes on involves complex three-dimensional relationships, in which sections of DNA become more or less accessible to gene-reading machinery. of the cell based on key signals, and in which some DNA strands form loops to form long-range interactions that allow stable readout of genes.

Some genes operate in chromatin “compartments” – protein complexes that house genes – that are open and active, while others are compacted and closed, as part of the “nuclear architecture.”

In the study, experiments confirmed that SARS-CoV-2 infection, and the immune reaction to it, decreases the ability of DNA strands in chromosomes that influence the formation of the olfactory receptor building to be open. and active, and to loop to activate gene expression.

In both hamster and human olfactory neuronal tissue, the research team detected a persistent and widespread downregulation of olfactory receptor construction.

Other work published by these authors suggests that olfactory neurons are connected to sensitive brain regions, and that ongoing immune cell reactions in the nasal cavity could influence emotions, and the ability to think clearly (cognition), which consistent with the long COVID.

Experiments conducted in hamsters and recorded over time revealed that receptor downregulation of olfactory neurons persisted after short-term changes that might affect the sense of smell had naturally recovered.

The authors state that this suggests that COVID-19 causes a more long-lasting disruption in chromosomal regulation of gene expression, representing a form of “nuclear memory” that could prevent restoration of OR transcription even after infection. elimination of SARS-CoV-2.

“The finding that the sense of smell depends on ‘fragile’ genomic interactions between chromosomes has important implications,” says tenOever.

“If olfactory gene expression ceases every time the immune system responds in certain ways that disrupt interchromosomal contacts, then the lost sense of smell could act like the ‘canary in the coal mine,’ providing any early signals that the COVID-19 virus is damaging brain tissue before other symptoms occur, and suggesting new ways to treat it,” he adds.

In a next step, the team is studying whether treating long-COVID hamsters with steroids can curb damaging immune reactions (inflammation) to protect nuclear architecture.