Coronavirus: Study finds further door opener into the cell

Date:
October 20, 2020
Source:
DZNE - German Center for Neurodegenerative Diseases
Summary:
The coronavirus SARS-CoV-2 is known to infect cells via the
receptor ACE2. Researchers have now identified neuropilin-1 as
a factor that can facilitate SARS-CoV-2 entry into the cells'
interior. Neuropilin-1 is localized in the respiratory and olfactory
epithelia.



FULL STORY ==========================================================================
The coronavirus SARS-CoV-2 is known to infect cells via the receptor
ACE2. An international research team under German-Finnish coordination has
now identified neuropilin-1 as a factor that can facilitate SARS-CoV-2
entry into the cells' interior. Neuropilin-1 is localized in the
respiratory and olfactory epithelia, which could be a strategically
important localization to contribute to SARS-CoV-2 infectivity and
spreading. Experts from the German Center for Neurodegenerative Diseases (DZNE), Technical University of Munich, University Medical Center
Goettingen, University of Helsinki and other research institutions now published their findings in the journal Science.


==========================================================================
The coronavirus SARS-CoV-2 can affect various organs such as the lung and kidneys and also trigger neurological symptoms, including a temporary loss
of smell and taste. The spectrum of symptoms of the associated disease
-- known as COVID-19 -- is therefore quite complex. A related virus,
SARS-CoV, led to a much smaller outbreak in 2003, possibly because the infection was limited to the lower respiratory system, making the virus
less transmissible. SARS-CoV-2, in contrast, additionally infects the
upper respiratory system including the nasal mucosa and, in consequence, spreads rapidly through active viral shedding, e.g. when sneezing.

Door opener to the cell Tissue tropism reflects the ability of a virus
to infect specific cell types in different organs. It is determined by
the availability of docking sites, so- called receptors, on the surface
of cells. These allow docking to and penetration into the cells. "The
starting point of our study was the question why SARS-CoV and SARS-CoV-2
that both use ACE2 as a receptor cause different diseases," explained
Mikael Simons, a research group leader at the DZNE's Munich site and
professor of molecular neurobiology at the Technical University of Munich, whose team was involved in the current studies, together with Giuseppe Balistreri's group at the University of Helsinki.

To understand how these differences in tissue tropisms can be explained,
the researchers took a look at the viral "spike proteins" that are
essential for virus entry. "The SARS-CoV-2 spike protein differs from
its older relative by the insertion of a furin cleavage site," explained Simons. "Similar sequences are found in the spike proteins of many other
highly pathogenic human viruses.

When we realized that this furin cleavage site is present in the SARS-CoV-
2 spike protein, we thought that this might lead us to the answer." When proteins are cleaved by furin, a specific amino acid sequence becomes
exposed at its cleaved end. Such furin cleaved substrates have a
characteristic pattern that are known to bind to neuropilins at the
cell surface.

Experiments using cells cultured in the laboratory, in conjunction with artificial viruses that mimick SARS-CoV-2 as well as naturally occurring
virus, indicate that neuropilin-1 is able to promote infection in the
presence of ACE2. By specifically blocking neuropilin-1 with antibodies, infection was suppressed. "If you think of ACE2 as a door to enter
the cell, then neuropilin- 1 could be a factor that directs the virus
to the door. ACE2 is expressed at very low levels in most cells. Thus,
it is not easy for the virus to find doors to enter. Other factors such
as neuropilin-1 might be necessary to help the virus," explained Simons.

A potential way into the nervous system Since loss of smell is among the COVID-19 symptoms and neuropilin-1 is mainly found in the cell layer of
the nasal cavity, the scientists examined tissue samples from deceased patients. "We wanted to find out whether cells equipped with neuropilin-1
are really infected by SARS-CoV-2, and found that this was the case," said Simons. Additional experiments in mice showed that neuropilin- 1 enables transport of tiny, virus-sized particles from the nasal mucosa to the
central nervous system. These nanoparticles were chemically engineered
to bind to neuropilin-1. When the nanoparticles were administered to
the nose of the animals, they reached neurons and capillary vessels of
the brain within few hours -- in contrast to control particles without
affinity for neuropilin-1.

"We could determine that neuropilin-1, at least under the conditions
of our experiments, promotes transport into the brain, but we cannot
make any conclusion on whether this is also true for SARS-CoV-2. It is
very likely that this pathway is suppressed by the immune system in most patients," explained Simons.

A starting point for future therapies? "SARS-CoV-2 requires the ACE2
receptor to enter the cells, but other factors such as neuropilin-1 may
be required to support its function," said Simons.

"However, at present we can only speculate about the molecular processes involved. Presumably, neuropilin-1 catches the virus and directs it
to ACE2.

Further investigations are needed to clarify this issue. It is currently
too early to speculate whether blocking neuropilin could be a viable therapeutic approach. This will have to be addressed in future studies."

========================================================================== Story Source: Materials provided by DZNE_-_German_Center_for_Neurodegenerative_Diseases.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ludovico Cantuti-Castelvetri, Ravi Ojha, Liliana D. Pedro, Minou
Djannatian, Jonas Franz, Suvi Kuivanen, Franziska van der Meer,
Katri Kallio, Tuğberk Kaya, Maria Anastasina, Teemu Smura, Lev
Levanov, Leonora Szirovicza, Allan Tobi, Hannimari Kallio-Kokko,
Pamela O"sterlund, Merja Joensuu, Fre'de'ric A. Meunier, Sarah
J. Butcher, Martin Sebastian Winkler, Brit Mollenhauer, Ari
Helenius, Ozgun Gokce, Tambet Teesalu, Jussi Hepojoki, Olli
Vapalahti, Christine Stadelmann, Giuseppe Balistreri, Mikael
Simons. Neuropilin-1 facilitates SARS-CoV- 2 cell entry and
infectivity. Science, Oct. 20, 2020; DOI: 10.1126/ science.abd2985 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201020105526.htm

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