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| Neuropilin-1 (NRP1) is a host factor for SARS-CoV-2 infection. The image shows human cells infected with SARS-CoV-2 and expressing viral proteins (shown in green). Removal of NRP1 from cells or treating cells with a drug or an antibody targeting NRP1 reduces SARS-CoV-2 infection Credit: University of Bristol |
Intelligent design creationist fans of the designer whom they believe created the SARS-CoV-2 virus that is currently causing the coronavirus pandemic, killing people by the hundreds of thousands, making millions more sick and wrecking economies as governments attempt to slow its progress and prevent medical services from being overwhelmed, will be thrilled to learn just what a thorough job it did this time, apparently having practiced first with SARS.
The malevolent brilliance of this designer can scarcely be imagined!
One of the puzzling things about SARS-CoV-2 is that it is so much more virulent than the closely related SARS virus and now two independent research teams have discovered why. Both viruses have a 'spike' protein on their outer coat which helps them bind to their victim's cells as a prelude to gaining entry into the cell, where it releases its RNA which converts the cell's reproductive machinery to making new viruses, killing the cell in the process. And yet, SARS-CoV-2 seems to be so much more successful at doing this.
The Bristol University press release explains:
Unlike other coronavirus, which cause common colds and mild respiratory symptoms, SARS-CoV-2, the causative agent of COVID-19, is highly infective and transmissive. Until now, major questions have remained unanswered as to why SARS-CoV-2 readily infects organs outside of the respiratory system, such as the brain and heart.
To infect humans, SARS-CoV-2 must first attach to the surface of human cells that line the respiratory or intestinal tracts. Once attached, the virus invades the cell then replicates multiple copies of itself. The replicated viruses are then released leading to the transmission of SARS-CoV-2.
The virus's process of attachment to and invasion of human cells is performed by a viral protein, called the ‘Spike’ protein. Understanding the process by which the ‘Spike’ protein recognises human cells is central to the development of antiviral therapies and vaccines to treat COVID-19.
In this breakthrough study, the research groups in Bristol’s Faculty of Life Sciences, Professor Peter Cullen from the School of Biochemistry; Dr Yohei Yamauchi, Associate Professor and virologist from the School of Cellular and Molecular Medicine, and Dr Boris Simonetti, a senior researcher in the Cullen lab, used multiple approaches to discover that SARS-CoV-2 recognises a protein called neuropilin-1 on the surface of human cells to facilitate viral infection.
Yohei, Boris and Pete explained: "In looking at the sequence of the SARS-CoV-2 Spike protein we were struck by the presence of a small sequence of amino acids that appeared to mimic a protein sequence found in human proteins which interact with neuropilin-1. This led us to propose a simple hypothesis: could the Spike protein of SARS-CoV-2 associate with neuropilin-1 to aid viral infection of human cells? Excitingly, in applying a range of structural and biochemical approaches we have been able to establish that the Spike protein of SARS-CoV-2 does indeed bind to neuropilin-1.
"Once we had established that the Spike protein bound to neuropilin-1 we were able to show that the interaction serves to enhance SARS-CoV-2 invasion of human cells grown in cell culture. Importantly, by using monoclonal antibodies - lab-created proteins that resemble naturally occurring antibodies - or a selective drug that blocks the interaction we have been able to reduce SARS-CoV-2’s ability to infect human cells. This serves to highlight the potential therapeutic value of our discovery in the fight against COVID-19."
The Bristol team's results were published yesterday in Science:
Abstract
SARS-CoV-2, the causative agent of COVID-19, uses the viral Spike (S) protein for host cell attachment and entry. The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates a polybasic Arg-Arg-Ala-Arg C-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2) receptors. Here, we used X-ray crystallography and biochemical approaches to show that the S1 CendR motif directly bound NRP1. Blocking this interaction using RNAi or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection and may potentially provide a therapeutic target for COVID-19.
Daly, James L.; Simonetti, Boris; Klein, Katja; Chen, Kai-En; Williamson, Maia Kavanagh; Antón-Plágaro, Carlos; Shoemark, Deborah K.; Simón-Gracia, Lorena; Bauer, Michael; Hollandi, Reka; Greber, Urs F.; Horvath, Peter; Sessions, Richard B.; Helenius, Ari; Hiscox, Julian A.; Teesalu, Tambet; Matthews, David A.; Davidson, Andrew D.; Collins, Brett M.; Cullen, Peter J.; Yamauchi, Yohei
Neuropilin-1 is a host factor for SARS-CoV-2 infection
Science 20 Oct 2020: eabd3072. DOI: 10.1126/science.abd3072
Copyright: © 2020 The authors. Published by The American Association for the Advancement of Science
Open access
Reprinted under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.
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| Cells cultured in the laboratory (cyan). Artificial viruses that mimic SARS-CoV-2 (magenta) infect the cell via ACE2 and neuropilin-1 Source: DZNE/Liliana Pedro-Domingues |
These findings were independently confirmed by a second team based in Munich, Germany and Helsinki, Finland. Their press release explains:
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.
This team also published their findings in Science yesterday.
Abstract
The causative agent of coronavirus induced disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. Here, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of human COVID-19 autopsies revealed SARS-CoV-2 infected cells including olfactory neuronal cells facing the nasal cavity positive for NRP1. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.
Cantuti-Castelvetri, Ludovico; Ojha, Ravi; Pedro, Liliana D.; Djannatian, Minou; Franz, Jonas; Kuivanen, Suvi; van der Meer, Franziska; Kallio, Katri; Kaya, Tuğberk; Anastasina, Maria; Smura, Teemu; Levanov, Lev; Szirovicza, Leonora; Tobi, Allan; Kallio-Kokko, Hannimari; Österlund, Pamela; Joensuu, Merja; Meunier, Frédéric A.; Butcher, Sarah J.; Winkler, Martin Sebastian; Mollenhauer, Brit; Helenius, Ari; Gokce, Ozgun; Teesalu, Tambet; Hepojoki, Jussi; Vapalahti, Olli; Stadelmann, Christine; Balistreri, Giuseppe; Simons, Mikael
Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity
Science 20 Oct 2020: eabd2985. DOI: 10.1126/science.abd2985
Open access
Reprinted under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.
Unfortunately, news of this finding was too late for inclusion in my latest book, The Malevolent Designer: Why Nature's God is not Good which list many more examples of what can only be described as the malevolence of any designer who could come up with this and so many other ways to cause chaos, misery and suffering to so much of the natural world, not just humans.
It seems then, if you believe in intelligent [sic] design, you have to believe the malevolent entity who designed the SARS-CoV-2 virus learned a lesson from its relative failure with the virus that caused SARS. By only infecting the lower respiratory tract, the virus did not get itself spread quickly and efficiently enough and has disappeared as a serious health threat, so the malevolent designer made some modifications and improvements in its Mark II version so it now invades the cells of the upper-respiratory tract and nasal mucosa so it can be spread more easily with coughs and sneezes and its ability to invade other cells makes it much more deadly.
Creationists are still caught in that terrible bind of either accepting that evolution by natural selection is the only explanation for this modification of a coronavirus to make it so deadly and damaging, that doesn't leave their deity looking like a malevolent, genocidal monster, or having people believe they worship this monster and look to it for moral guidance.
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