Mechanism revealed behind loss of smell with COVID-19

Date:
February 2, 2022
Source:
NYU Langone Health / NYU Grossman School of Medicine
Summary:
Researchers have discovered a mechanism that may explain why
COVID-19 patients lose their sense of smell, as well as having
implications for long COVID.



FULL STORY ========================================================================== Researchers have discovered a mechanism that may explain why COVID-19
patients lose their sense of smell.


========================================================================== Published online February 2 in the journalCell, the new study found that infection with the pandemic virus, SARS-CoV-2, indirectly dials down the
action of olfactory receptors (OR), proteins on the surfaces of nerve
cells in the nose that detect the molecules associated with odors.

Led by researchers from NYU 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 lingering neurological
effects of COVID-19 like "brain fog," headaches, and depression.

Experiments showed that the presence of the virus near nerve cells
(neurons) in olfactory tissue brought an inrushing of immune cells,
microglia and T cells, that sense and counter infection. Such cells
release proteins called cytokines that changed the genetic activity of olfactory nerve cells, even though the virus cannot infect them, say the
study authors. Where immune cell activity would dissipate quickly in
other scenarios, in the brain, according to the team's theory, immune
signaling persists in a way that reduces the activity of genes needed
for the building of olfactory receptors.

"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 author Benjamin tenOever, PhD, professor in the Department of Microbiology at NYU Langone Health. "The work, in addition
to another study from the tenOever group, also suggests how the pandemic
virus, which infects less than 1 % of cells in the human body, can cause
such severe damage in so many organs." Change in Architecture One unique symptom of COVID-19 infection is loss of smell without the stuffy nose
seen with other infections like the common cold, researchers say. In
most cases, the smell loss lasts only a few weeks, but for more than
12 percent of COVID-19 patients, olfactory dysfunction persists in the
form of ongoing reduction in the ability to smell (hyposmia) or changes
in how a person perceives the same smell (parosmia).



==========================================================================
To gain insight into COVID-19-induced smell loss, 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, being mammals that both depend more on the
sense of smell than humans, and that are more susceptible to nasal
cavity infection.

The study results build on the discovery over many years that the
process which turns genes on involves complex 3-D relationships, where
DNA sections become more or less accessible to the cell's gene-reading machinery based on key signals, and where some DNA chains loop around to
form long-range interactions that enable the stable reading of genes. Some genes operate in chromatin "compartments" -- protein complexes that house
the genes -- that are open and active, while others are compacted and
closed, as part of the "nuclear architecture." In the current study, experiments confirmed that SARS-CoV-2 infection, and the immune reaction
to it, decreases the ability of DNA chains in chromosomes that influence
the formation of olfactory receptor building to be open and active,
and to loop around to activate gene expression. In both hamster and
human olfactory neuronal tissue, the research team detected persistent
and widespread downregulation of olfactory receptor building. Other work
posted by these authors suggests that olfactory neurons are wired into sensitive brain regions, and that ongoing immune cell reactions in the
nasal cavity could influence emotions, and the ability to think clearly (cognition), consistent with long COVID.

Experiments in hamsters recorded over time revealed that downregulation of olfactory neuron receptors persisted after short-term changes that might
affect the sense of smell had naturally recovered. The authors say this suggests that COVID-19 causes longer-lasting disruption in chromosomal regulation of gene expression, representing a form of "nuclear memory"
that could prevent the restoration of OR transcription even after
SARS-CoV-2 is cleared.

"The realization that the sense of smell relies 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 disrupts inter-chromosomal contacts, then the lost
sense of smell may act as the "canary in the coalmine," providing any
early signals that the COVID-19 virus is damaging brain tissue before
other symptoms present, and suggesting new ways to treat it." In a
next step, the team is looking into whether treating hamsters with long
COVID with steroids can restrain damaging immune reactions (inflammation)
to protect nuclear architecture.

Along with tenOever, authors of the current study from the Department
of Microbiology at NYU Langone Health were Justin Frere, Rasmus
Moeller, Skyler Uhl, and Daisy Hoagland. Also leading the study were corresponding authors Jonathan Overdevest and Stavros Lomvardas from the Mortimer B. Zuckerman Mind, Brain and Behavior Institute at Columbia University. Additional contributors included Marianna Zazhytska,
Albana Kodra, Hani Shayya, Stuart Firestein, Peter Canoll, and James
Goldman. Also making important contributions were study authors John
Fullard and Panos Roussos of the Icahn School of Medicine at Mt.

Sinai; Arina Omer of Baylor Genetics in Houston; and Qizhi Gong of
the Department of Cell Biology and Human Anatomy, School of Medicine, University of California at Davis. Funding for the study was provided
by National Institutes of Health grants NIDCD 3R01DC018744-01S1 and U01DA052783, as well as by a Howard Hughes Medical Institute Faculty
Scholar Award and the Zegar Family Foundation.

special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by NYU_Langone_Health_/_NYU_Grossman_School_of_Medicine.

Note: Content may be edited for style and length.


========================================================================== Journal References:
1. Marianna Zazhytska, Albana Kodra, Daisy A. Hoagland, Justin
Frere, John
F. Fullard, Hani Shayya, Natalie G. McArthur, Rasmus Moeller,
Skyler Uhl, Arina D. Omer, Max E. Gottesman, Stuart Firestein,
Qizhi Gong, Peter D.

Canoll, James E. Goldman, Panos Roussos, Benjamin R. tenOever,
Jonathan B. Overdevest, Stavros Lomvardas. Non-cell autonomous
disruption of nuclear architecture as a potential cause of COVID-19
induced anosmia.

Cell, 2022; DOI: 10.1016/j.cell.2022.01.024
2. Daisy A. Hoagland, Rasmus Mo/ller, Skyler A. Uhl, Kohei Oishi,
Justin
Frere, Ilona Golynker, Shu Horiuchi, Maryline Panis, Daniel
Blanco-Melo, David Sachs, Knarik Arkun, Jean K. Lim, Benjamin
R. tenOever. Leveraging the antiviral type I interferon system as
a first line of defense against SARS-CoV-2 pathogenicity. Immunity,
2021; 54 (3): 557 DOI: 10.1016/ j.immuni.2021.01.017 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220202124320.htm

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