Coronovirus 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 interior of cells. Neuropilin-1 localizes in the respiratory and olfactory epithelium, which may be a strategically important localization to contribute to SARS-COV-2 infectivity and proliferation. Specialists at the German Center for Neurodegenerative Diseases (DZNE), Technical University of Munich, University Medical Center Goettingen, University of Helsinki and other research institutes have now published their findings in the journal. Science.
Coronovirus SARS-CoV-2 can affect various organs such as the lungs and kidneys and also trigger neurological symptoms, including temporary loss of smell and taste. The spectrum of associated disease symptoms — called COVID-19, is therefore quite complex. A related virus, SARS-CoV, caused a very small outbreak in 2003, probably because the infection was restricted to the lower respiratory system, making the virus less transmitted. In contrast, SARS-CoV-2, furthermore, infects the upper respiratory system including the nasal mucosa and, as a result, spreads rapidly through active viral shedding, such as on sneezing.
Door opener in cell
Tissue tropism refers to the ability to infect specific types of viruses in different cells. This is determined by the availability of docking sites, the so-called receptors on the surface of cells. These allow docking and entering cells. “The starting point of the study was the question of whether SARS-CoV and SARS-CoV-2 that both use ACE2 as a receptor cause various diseases,” the leader of the Munich site research group of DZNE and Molecular Neurobiology Professor Mikel Simons explained. At the Technical University of Munich, whose team was involved in the current study, there was also a group of Giuseppe Ballesari at the University of Helsinki.
To understand how these differences in tissue tropism might be explained, researchers took a look at the viral “spike proteins” that are essential for the entry of the virus. “The SARS-Cove-2 spike protein differs from its older relative by the insertion of a furin cleavage site,” Simmons explained. “Similar sequences are found in the spike proteins of many other pathogenic human viruses. When we realized that this furin cleavage site is present in the SARS-CoV-2 spike protein, we thought it might give us the answer.” When the protein is cleavaged by furin, a specific amino acid sequence is exposed at its cleaved end. Such furin is a characteristic pattern of cleaved substrates that are known to bind to neuropilins on the cell surface.
The use of laboratory-cultured cells in combination with SARS-CoV-2 as well as artificial viruses mimicking naturally found viruses indicate that neuropilin-1 is capable of promoting infection in the presence of ACE2 . Infection was suppressed by specifically blocking neuropilin-1 with antibodies. “If you think of ACE2 as a door to enter the cell, then neuropilin-1 may be a factor that directs the virus to the door. ACE2 is at very low levels in most cells Is expressed. Thus, it is not easy for the virus. To find the doors to enter. Other factors such as neuropilin-1 may be necessary to help the virus, “Simmons explained.
A possible way in the nervous system
Since odor loss is one of the symptoms of COVID-19 and neuropilin-1 is mainly found in the cell layer of the nasal cavity, scientists examined tissue samples from deceased patients. “We wanted to find out if cells equipped with neuropilin-1 were actually infected with SARS-CoV-2, and found that was the case,” Simmons said. Additional experiments in mice showed that neuropilin-1 enables the transport of small, virus-sized particles from the nasal mucosa to the central nervous system. These nanoparticles were chemically engineered to bind to neuropilin-1. When nanoparticles were administered from the nostrils of animals, they reached brain neurons and capillary vessels within a few hours, as opposed to controlling the particle without affinity for neuropilin-1. “We can determine that neuropiline-1 promotes transport in the brain, at least under the conditions of our experiments, but we cannot conclude that it is also for SARS-CoV-2 True or not. It is very likely that this is the tract. In most patients the immune system is suppressed, “Simmons explained.
A starting point for future treatments?
“SARS-CoV-2 requires the ACE2 receptor to enter cells, but other factors such as neuropilin-1 may be required to support its function,” Simmons said. “However, at present we can only speculate about involvement in molecular processes. Presumably, neuropilin-1 captures the virus and directs it to ACE2. Further investigation is needed to clarify this issue. . It is currently too early to speculate whether neuropiline can be inhibited. A viable therapeutic approach. This will have to be addressed in future studies. ”
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Ludovico Cantuti-Castellvari et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 20 October 2020: DOI: 10.1126 / science.bd 2985
Provided by the German Center for Neurodegenerative Diseases
Quotes: Coronavirus: study finds front door opener in cell (2020, 20 October) from 21 October 2020 https://medicalxpress.com/news/2020-10-coronavirus-door-cell.html
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