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The SARS-CoV-2 coronavirus is known to infect cells through the ACE2 receptor. An international research team under German-Finnish coordination has identified neuropilin-1 as a factor that can facilitate the entry of SARS-CoV-2 into cells. Neuropilin-1 is located in the respiratory and olfactory epithelia, which could be a strategically important location to contribute to the infectivity and spread of SARS-CoV-2. Experts from the German Center for Neurodegenerative Diseases (DZNE), the Technical University of Munich, the Goettingen University Medical Center, the University of Helsinki and other research institutions have now published their findings in the journal “Sciences“.
The SARS-CoV-2 coronavirus can affect various organs such as the lungs 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, caused 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, on the other hand, further infects the upper respiratory system, including the nasal mucosa, and consequently spreads rapidly through active viral shedding, for example, by sneezing.
Door opener to 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 coupling and penetration into the cells. “The starting point of our study was the question of why SARS-CoV and SARS-CoV-2, which use ACE2 as a receptor, cause different diseases,” explained Mikael Simons, leader of the research group at the site of Munich of the DZNE 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 looked at 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,” Simons explained. “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 spike protein of SARS-CoV-2, we thought this might lead us to the answer “. When proteins are cleaved by furin, a specific amino acid sequence is exposed at their cleaved end. Such furin-cleaved substrates have a characteristic pattern that is known to bind to neuropilins on the cell surface.
Experiments using cells grown in the laboratory, along with man-made viruses that mimic SARS-CoV-2, as well as naturally-occurring viruses, indicate that neuropilin-1 can promote infection in the presence of ACE2. By specifically blocking neuropilin-1 with antibodies, the infection was suppressed. “If you think of ACE2 as a gate to enter the cell, then neuropilin-1 could be a factor that directs the virus to the gate. ACE2 is expressed at very low levels in most cells. Therefore, it does not it’s easy for the virus to find gates to get in. Other factors like neuropilin-1 might be needed to help the virus, “explained Simons.
A potential pathway to the nervous system.
Since loss of smell is among the symptoms of COVID-19 and neuropilin-1 is primarily found in the cell layer of the nasal cavity, the scientists examined tissue samples from deceased patients. “We wanted to find out if the cells equipped with neuropilin-1 are actually infected by SARS-CoV-2, and we found that this was the case,” Simons said. Additional experiments in mice showed that neuropilin-1 enables the 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 delivered to the animals’ noses, they reached neurons and capillaries in the brain within a few hours, in contrast to control particles with no affinity for neuropilin-1. “We could determine that neuropilin-1, at least under the conditions of our experiments, promotes transport to the brain, but we cannot draw any conclusion as to 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 cells, but other factors such as neuropilin-1 may be required to support its function,” Simons said. “However, at present we can only speculate about the molecular processes involved. Presumably, neuropilin-1 traps the virus and directs it to ACE2. More research is needed to clarify this problem. It is currently too early to speculate whether the block of neuropilin could be a viable therapeutic approach. This should be addressed in future studies. “
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Original post
Neuropilin-1 facilitates the entry and infectivity of SARS-CoV-2 cells, Ludovico Cantuti-Castelvetri et al., Sciences (2020), DOI: https: /
About the German Center for Neurodegenerative Diseases (DZNE)
The DZNE investigates all aspects of neurodegenerative diseases (such as Alzheimer’s and Parkinson’s and amyotrophic lateral sclerosis) in order to develop new approaches to prevention, treatment and health care. The DZNE is made up of ten sites in Germany and cooperates closely with universities, university hospitals and other institutions on a national and international level. The DZNE is a member of the Helmholtz Association. Website: http: // www.
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