BREAKING! News-COVID-19: Study Shows That SARS-CoV-2 Can Bind To Human Host Neuropilin-1 Receptor (NRP-1), Blocking Certain Pain Signals In Host!
: A new study by researchers from University of Arizona-Tucson led by Dr Rajesh Khanna, Professor from the department of pharmacology has made a breakthrough discovery that the SARS-CoV-2 is also able to bind to the neuropilin-1 receptors in humans,(NRP-I) in the process disrupting certain pain signals pathways, hence making the human host impervious to pain that might otherwise be critical to alert to any resulting organ or tissue infections and damage! A ‘silencing’ of pain via subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.
To put it in simple terms, the deadly SARS-CoV-2 is capable of infecting a person, making them impervious to pain while damaging their organs and tissues and by the time the discovery it could be just late and infections could have spread far and wide.
Such is the ever evolving SARS-CoV-2 coronavirus, an anomalous virus that is like no other.
The research findings were published on a preprint server and has already been peer-reviewed and due for publication in the Journal soon. https://www.biorxiv.org/content/10.1101/2020.07.17.209288v3
Update: Published into Pain Journal:
The research findings has numerous implications as it shows that besides the normal route of entering cells through the ACE receptors, The SARS-CoV-2 coronaviris us able to enter the nervous system using the neuropilin-1 receptors (NRP-1).
The study findings also could also justify as to why some people are asymptomatic and hence people infected with SARS-CoV-2, the virus causing COVID-19, may be spreading the disease without knowing it.
Professor Khanna is a neurology researcher
who studies how proteins on cells trigger pain signals that are transmitted through the body to the brain.When these proteins are active, the nerve cells are communicating to each other. In chronic pain scenarios, this ‘conversation’ occurs at deafening levels.
Hence simply by studying what causes the excitability of nerve cells to change,scientist can begin to unravel how chronic pain becomes established. This also allows them to design ways to mute this conversation to blunt or stop chronic pain.
Dr Khanna’ lab has a longstanding interest in designing nonopioid-based alternatives for pain management.
He and the rest of the study team were intrigued by two past European studies that indicated the spike proteins on the surface of the SARS-CoV-2 coronavirus could bind to a protein called neuropilin-1. https://www.biorxiv.org/content/10.1101/2020.06.05.134114v1
Once validated, this implies that the SARS-CoV-2 coronavirus can also use the same protein to invade nerve cells directly besides using the ACE2 receptors.
Dr Khanna’s team had been studying role of neuropilin-1 in the context of pain perception for months prior to the COVID-19 pandemic.
Hence the team decided to validate if the SARS-CoV-2 coronavirus not only could bind directly to the neuropilin-1 receptors but also if there was any relation to pain.
Typically under normal circumstances, the neuropilin-1 protein controls the growth of blood vessels, and as well as the growth and survival of neurons.
But studies have shown that when neuropilin-1 binds to a naturally occurring protein called called Vascular endothelial growth factor A (VEGF-A), this triggers pain signals. This signal is transmitted via the spinal cord into higher brain centers to cause the sensation we all know as pain.
Dr Khanna’s study team decided to study if there was a link between neuropilin and spike and also pain since the neuropilin-1 and VEGF-A link was already confirmed associated to pain.
Past research has shown a link between VEGF-A and pain. For individuals with osteoarthritis, for instance, studies have shown that increased activity of the VEGF gene in fluids lubricating joints, like the knee, is associated with higher pain scores. https://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/s12891-018-2127-2
Despite activity of the neuropilin-1 gene is higher in biological samples from COVID-19 patients compared to healthy controls and activity of the neuropilin-1 gene is increased in pain-sensing neurons in an animal model of chronic pain, the role of neuropilin-1 in pain has never been explored until now.
The research at Dr Khana’s involving vitro studies using nerve cells, showed that when spike binds to neuropilin-1 it decreases pain signaling, which suggests that in a living animal it would also have a pain-dulling effect.
It was found that when the spike protein binds to the neuropilin-1 protein, it blocks the VEGF-A protein from binding and thus hijack's a cell's pain circuitry. This binding suppresses the excitability of pain neurons, leading to lower sensitivity to pain.
The study team said that further research confirming the finding that the SARS-CoV-2coronavirus is attacking cells through a protein associated with pain and disabling the protein in humans may provide a new pathway for drug development to treat COVID-19.
It is already known that a small molecule, called EG00229, targeting neuropilin-1 had been reported in a 2018 study. This molecule binds to the same region of the neuropilin-1 protein as the viral spike protein and VEGF-A. https://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/s12891-018-2127-2
Dr Khanna’s study team had already confirmed in past research that this molecule was able to block pain. It was demonstrated during pain simulations in rats. Their study data also reaffirmed the notion of neuropilin-1 as a new player in pain signaling.
Interestingly there is precedence for targeting the neuropilin-1 protein for cancer treatment: for example, a Phase 1a clinical trial of an antibody called MNRP1685A (known under the product name Vesencumab) that recognizes and binds to neuropilin-1 and blocks VEGF-binding. This was mostly well tolerated in cancer patients, but it caused pain rather than blocking it. https://clinicaltrials.gov/ct2/show/NCT00747734
Dr Khanna’s studies however identify a different approach because they targeted blocking the pain-triggering VEGF-A protein, which then resulted in pain relief.
The study findings described here provides a rationale for targeting the VEGF-A/NRP-1 pro-pain signaling system in future clinical trials.
Detailed analysis of the structure of the neuropilin-1 receptor protein may allow design of drugs targeting this critical site which also controls axon growth, cell survival in addition to pain relief.
Significantly these neuropilin-1 receptor targeted drugs could potentially block viral infection. The testing of several drug candidates, some of them on the FDA's generally regarded as safe list, is currently underway by Dr Khanna’s study team and could result in some being repurposed to treat COVID-19.
Dr Khanna’s study data showed that SARS-CoV-2 Spike protein subverts VEGF-A/NRP-1 pronociceptive signaling. Relevant to chronic neuropathic pain, Spike negated VEGF-A–mediated increases in: (i) voltage-gated sodium and N-type calcium current densities in DRG neurons; (ii) spontaneous firing in DRG neurons; (iii) spinal neurotransmission; and (iv) mechanical allodynia and thermal hyperalgesia. Consequently, Spike protein was analgesic in a nerve injury rat model. Based on the reported increase in VEGF-A levels in COVID-19 patients, one would expect to observe increased pain-related symptoms.
However, the study data suggest that the SARS-CoV-2 Spike protein hijacks NRP-1 signaling to ameliorate VEGF-A mediated pain. This raises the possibility that pain, as an early symptom of COVID-19, may be directly dampened by the SARS-CoV-2 Spike protein.
The research results do not exclude the possibility that alternative fragments of Spike or other viral proteins may be pro-nociceptive. Leveraging this atypical function of SARS-CoV-2 Spike protein may yield a novel class of therapeutics for pain.
As Dr Khanna says, the coronavirus is extremely ‘sneaky’, by giving individuals the perception that they do not have the COVID-19 disease while damaging them even more.
From the study it emerges that blocking neuropilin-1 receptors may also to limit SARS-CoV-2 entry.
But as far as treating COVID-19 is concerned, it might need an assortment of drugs as the virus has a variety of receptors to gain entry into the host body and also have so many ways of interacting with the various cellular pathways and processes in the human host body.
Coupled with the fact the SARS-CoV-2 is ever evolving and always staying far more ahead of the game, it seems that the COVID-19 pandemic is going to be around for a long while with ever increasing severity and effects though some may not be apparent immediately due to the ‘smart nature’ of the virus.
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