New study reveals why COVID-19 often causes loss of smell

NEW YORK — Loss of smell has been synonymous with COVID-19 since the very beginning of the pandemic. Now, scientists from New York University and Columbia University report the discovery of a “mechanism” that may explain COVID-connected loss of smell.

In short, the new study finds that SARS-CoV-2 dampens and dials down the body’s olfactory receptors in an indirect manner. Those receptors are actually proteins on the surfaces of nerve cells in the nose, detecting and deciphering odor molecules. In simpler terms, the coronavirus flips our odor-detecting cells into “off mode.”

These findings are relevant beyond just COVID-19 symptoms that affect the sense of smell. Researchers explain this work may offer additional clues regarding COVID-19’s mysterious impact on other types of brain cells, as well as lingering post-COVID symptoms such as brain fog, headaches, and even depression.

COVID impacts the nerve cells

Experiments conducted for this project showed that when the coronavirus gets close to nerve cells (neurons) in olfactory tissues, the immune system responds with an influx of immune cells, microglia, and T cells to fight the infection. Those well-intentioned immune cells then release proteins called cytokines that end up altering the very genetic activity of olfactory nerve cells. The irony in all of this is that SARS-CoV-2 isn’t capable of actually infecting the olfactory nerve cells.

Normally, immune cell activity in such a situation would slow down rather quickly. However, study authors theorize that in this case, within the brain, immune signaling continues and persists to the point that activity among the genes necessary for the building of olfactory receptors suffers considerably.

“Our findings provide the first mechanistic explanation of smell loss in COVID-19 and how this may underlie long COVID-19 biology,” says co-corresponding study author Benjamin tenOever, PhD, professor in the Departments of Medicine and Microbiology at NYU Langone Health, in a university release. “The work, in addition to another study from the tenOever group, also suggests how the pandemic virus, which infects less than 1 percent of cells in the human body, can cause such severe damage in so many organs.”

Why does loss of smell continue after COVID?

While loss of smell can happen with much milder respiratory conditions like the common cold, what separates COVID-related loss of smell is the lack of congestion within the nose. For many COVID-19 patients, loss of smell dissipates over the course of a few weeks. Others, however, aren’t as lucky. They experience smell issues for months upon months. Roughly 12 percent of COVID-19 patients report a persistent reduction in their ability to smell (hyposmia) or long-lasting changes in how they perceive certain smells (parosmia).

To research this troubling phenomenon, study authors investigated the “molecular consequences” of a SARS-CoV-2 infection among a collection of golden hamsters. The team also analyzed olfactory tissues taken from 23 human autopsies. While the inclusion of hamsters may seem strange, these rodents were actually perfect for the study because they’re mammals that rely on their sense of smell far more than humans. Hamsters are also generally more vulnerable to nasal cavity infections.

Experiments conducted by the research team confirmed that SARS-CoV-2 infection, and the human body’s subsequent immune reaction to that infection, decreases the ability of certain DNA chains in chromosomes to open up, activate, loop around, and eventually turn on their gene expressions. This is important because those DNA chains are responsible for the formation of olfactory receptor building.

In both human and hamster olfactory neuronal tissues, researchers observed “persistent and widespread downregulation of olfactory receptor building.”

‘Nuclear memory’ may explain long COVID symptoms

Additional research conducted by the team also indicates olfactory neurons are wired into and connected with sensitive brain regions. This suggests that continuous immune activity within the nose may impact both emotional control and diminish cognition, both of which are common long-COVID symptoms.

Over time, further experiments with the hamsters even showed that decreases in the capacities of olfactory neuron receptors continue even after other short-term changes that may affect sense of smell have dissipated. In summation, study authors conclude this strongly indicates that COVID-19 can result in very long-lasting disruptions in the chromosomal regulation of gene expression. This form of “nuclear memory” may be what is stopping so many people from regaining their old sense of smell despite recovering from COVID-19 weeks and months earlier.

“The realization that the sense of smell relies on ‘fragile’ genomic interactions between chromosomes has important implications,” Dr. tenOever concludes. “If olfactory gene expression ceases every time the immune system responds in certain ways that disrupts inter-chromosomal contacts, then the lost sense of smell may act as the ‘canary in the coal mine,’ providing early signals that the COVID-19 virus is damaging brain tissue before other symptoms present, and suggesting new ways to treat it.”

Moving forward, the research team is preparing further trials aimed at determining if treating hamsters suffering from long-COVID with steroids can help resolve symptoms.

The study is published in the journal Cell.

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