NEW YORK, Feb. 2, 2022 /PRNewswire/ -- Published online
February 2 in the journal
Cell, 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.
Contact:
Gregory Williams
gregory.williams@nyulangone.org
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SOURCE NYU Langone Health