Temporary loss of
smell, or anosmia, is the main neurological symptom and one of the earliest and
most commonly reported indicators of COVID-19. Studies suggest it better
predicts the disease than other well-known symptoms such as fever and cough,
but the underlying mechanisms for loss of smell in patients with COVID-19 have
been unclear.
Now, an international team of researchers led by
neuroscientists at Harvard Medical School has identified the olfactory cell
types most vulnerable to infection by SARS-CoV-2, the virus that causes
COVID-19.
Surprisingly, sensory neurons that detect and transmit
the sense of smell to the brain are not among the vulnerable cell types.
Reporting in Science
Advances on July 24, the research team found that olfactory
sensory neurons do not express the gene that encodes the ACE2 receptor protein,
which SARS-CoV-2 uses to enter human cells. Instead, ACE2 is expressed in cells
that provide metabolic and structural support to olfactory sensory neurons, as
well as certain populations of stem cells and blood vessel cells.
The findings suggest that infection of nonneuronal cell
types may be responsible for anosmia in COVID-19 patients and help inform
efforts to better understand the progression of the disease.
“Our findings indicate that the novel coronavirus
changes the sense of smell in patients not by directly infecting neurons but by
affecting the function of supporting cells,” said senior study author Sandeep
Robert Datta, associate professor of neurobiology in the Blavatnik Institute at
HMS.
This implies that in most cases, SARS-CoV-2 infection
is unlikely to permanently damage olfactory neural circuits and lead to
persistent anosmia, Datta added, a condition that is associated with a variety
of mental and social health issues, particularly depression and anxiety.
“I think it’s good news, because once the infection
clears, olfactory neurons don’t appear to need to be replaced or rebuilt from
scratch,” he said. “But we need more data and a better understanding of the
underlying mechanisms to confirm this conclusion.”
A majority of COVID-19 patients experience some level
of anosmia, most often temporary, according to emerging data. Analyses of
electronic health records indicate that COVID-19 patients are 27 times more
likely to have smell loss but are only around 2.2 to 2.6 times more likely to
have fever, cough or respiratory difficulty, compared to patients without
COVID-19.
Some studies have hinted that anosmia in COVID-19
differs from anosmia caused by other viral infections, including by other
coronaviruses.
For example, COVID-19 patients typically recover their
sense of smell over the course of weeks — much faster than the months it can
take to recover from anosmia caused by a subset of viral infections known to
directly damage olfactory sensory neurons. In addition, many viruses cause
temporary loss of smell by triggering upper respiratory issues such as stuffy
nose. Some COVID-19 patients, however, experience anosmia without any nasal
obstruction.
Pinpointing
vulnerability
In the current study, Datta and colleagues set out to
better understand how sense of smell is altered in COVID-19 patients by
pinpointing cell types most vulnerable to SARS-CoV-2 infection.
They began by analyzing existing single-cell
sequencing datasets that in total catalogued the genes expressed by hundreds of
thousands of individual cells in the upper nasal cavities of humans, mice and
nonhuman primates.
The team focused on the gene ACE2, widely found in
cells of the human respiratory tract, which encodes the main receptor protein
that SARS-CoV-2 targets to gain entry into human cells. They also looked at
another gene, TMPRSS2, which encodes an enzyme thought to be important for
SARS-CoV-2 entry into the cell.
The analyses revealed that both ACE2 and TMPRSS2 are
expressed by cells in the olfactory epithelium — a specialized tissue in the
roof of the nasal cavity responsible for odor detection that houses olfactory
sensory neurons and a variety of supporting cells.
Neither gene, however, was expressed by olfactory
sensory neurons. By contrast, these neurons did express genes associated with
the ability of other coronaviruses to enter cells.
The researchers found that two specific cell types in
the olfactory epithelium expressed ACE2 at similar levels to what has been
observed in cells of the lower respiratory tract, the most common targets of
SARS-CoV-2, suggesting a vulnerability to infection.
These included sustentacular cells, which wrap around
sensory neurons and are thought to provide structural and metabolic support,
and basal cells, which act as stem cells that regenerate the olfactory
epithelium after damage. The presence of proteins encoded by both genes in
these cells was confirmed by immunostaining.
In additional experiments, the researchers found that
olfactory epithelium stem cells expressed ACE2 protein at higher levels after
artificially induced damage, compared with resting stem cells. This may suggest
additional SARS-CoV-2 vulnerability, but it remains unclear whether or how this
is important to the clinical course of anosmia in patients with COVID-19, the
authors said.
Datta and colleagues also analyzed gene expression in
nearly 50,000 individual cells in the mouse olfactory bulb, the structure in
the forebrain that receives signals from olfactory sensory neurons and is
responsible for initial odor processing.
Neurons in the olfactory bulb did not express ACE2.
The gene and associated protein were present only in blood vessel cells,
particularly pericytes, which are involved in blood pressure regulation,
blood-brain barrier maintenance and inflammatory responses. No cell types in
the olfactory bulb expressed the TMPRSS2 gene.
Smell
loss clue
Together, these data suggest that COVID-19-related
anosmia may arise from a temporary loss of function of supporting cells in the
olfactory epithelium, which indirectly causes changes to olfactory sensory
neurons, the authors said.
“We don’t fully understand what those changes are yet,
however,” Datta said. “Sustentacular cells have largely been ignored, and it
looks like we need to pay attention to them, similar to how we have a growing
appreciation of the critical role that glial cells play in the brain.”
The findings also offer intriguing clues into
COVID-19-associated neurological issues. The observations are consistent with
hypotheses that SARS-CoV-2 does not directly infect neurons but may instead
interfere with brain function by affecting vascular cells in the nervous
system, the authors said. This requires further investigation to verify, they
added.
The study results now help accelerate efforts to
better understand smell loss in patients with COVID-19, which could in turn
lead to treatments for anosmia and the development of improved smell-based
diagnostics for the disease.
“Anosmia seems like a curious phenomenon, but it can
be devastating for the small fraction of people in whom it’s persistent,” Datta
said. “It can have serious psychological consequences and could be a major
public health problem if we have a growing population with permanent loss of
smell.”
The team also hope the data can help pave inroads for
questions on disease progression such as whether the nose acts as a reservoir
for SARS-CoV-2. Such efforts will require studies in facilities that allow
experiments with live coronavirus and analyses of human autopsy data, the
authors said, which are still difficult to come by. However, the collaborative
spirit of pandemic-era scientific research calls for optimism.
“We initiated this work because my lab had a couple of
datasets ready to analyze when the pandemic hit, and we published an initial
preprint,” Datta said. “What happened after that was amazing, researchers
across the globe offered to share and merge their data with us in a kind of
impromptu global consortium. This was a real collaborative achievement.”
Source: https://myfusimotors.com/2020/07/27/how-covid-19-causes-smell-loss/
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