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The ongoing COVID-19 pandemic is caused by betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing a spectrum of illnesses ranging from asymptomatic to critical. The rapid transmission of the virus is responsible for the difficulty in containing it, together with the significant percentage of asymptomatic transmission.
A recent study published in the journal Pain in October 2020 adds another piece to the puzzle, showing that the virus is capable of obstructing pain pathways. This can contribute to its early and extensive spread.
Asymptomatic patients and the spread of COVID-19
Asymptomatic and minimally symptomatic patients account for ~ 40% of all SARS-CoV-2 cases, according to recent data published by the US Centers for Disease Control and Prevention, and about half of all transmission occurs before the earliest symptom onset. Therefore, these individuals are efficient spreaders of the virus, which has created enormous challenges in preventing viral transmission. On the other hand, symptomatic patients often suffer from pain, such as headache, myalgia, arthralgia, and abdominal discomfort.
The question being asked here is, do asymptomatic or minimally symptomatic patients also have the same viral processes, or are pain pathways somehow silenced?
The virus enters and infects the host cell after binding to angiotensin-converting enzyme 2 (ACE2), the virus receptor on the host cell. However, there is a smaller group of neurons in which the ACE2 receptor is expressed, which connects to the spinal column and brain stem neurons. They are believed to be responsible for headaches and nerve pain; however, few neurons in total express ACE2.
Alternatives to ACE2
ACE2 levels are lower with age, although this is inversely correlated with the severity of the disease. This may suggest that there are other receptors besides ACE2 to mediate viral cell binding.
In fact, two reports have recently shown that the spike protein of the virus binds to a receptor called neuropilin receptor-1 (NRP-1), in the b1b2 domain. The region responsible for this binding is a polybasic sequence not found in SARS viruses or MERS, and is called the C-end rule. This interaction promotes viral entry into the cell.
Analysis of proteins, transcribed RNA fragments, and other cellular processes show that the level of NRP-1 is higher in samples from COVID-19 patients than in healthy individuals.
Importance of VEGF-A
Under physiological conditions, the b1b2 domain is bound by a factor called VEGF-A (vascular endothelial growth factor A), which is important in both inflammation and wound healing. Therefore, the researchers explored whether the presence of the SARS-CoV-2 spike protein inhibits the binding of this ligand to its receptor, and thus affects signaling through pain pathways.
In both rodents and humans, VEGF-A is known to promote pain sensation. This factor is found at elevated levels in the bronchial alveolar lavage fluid obtained from COVID-19 patients, but there is a significantly lower level in the serum of asymptomatic patients compared to symptomatic individuals. Therefore, the researchers also explored whether the spike protein could also make the sensation of pain decrease.
Binding to NRP-1 induces pain
The researchers found that when the NRP-1 receptor binds to its VEGF-A ligand, it increases the spontaneous activation rate of dorsal root ganglion (DRG) neurons. This was blocked by the S1 domain of the spike protein and by the NRP-1 inhibitor EG00229.
Other ligands for receptors that act as coreceptors for NRP-1 failed to enhance the activation of these nociceptive cells. Therefore, this indicates a new pathway for pain, namely the VEGF-A ligand and the NRP-1 receptor.
The viral spike protein binds to the same binding pocket in NRP-1, preventing pain signaling through this pathway. Although it was confirmed that VEGF-A potentiates the sensation of pain after mechanical and thermal stimuli, these actions were blocked by the binding of the NRP-1 receptor by the spike protein or the NRP-1 inhibitor EG00229. However, none of these are effective against pain on their own.
Peak protein inhibits VEGF-A-mediated increase in DRG ion currents
The researchers found that VEGF-A binding doubled the total sodium and calcium ion currents in DRG neurons, but this was also blocked by spike protein and the NRP-1 inhibitor EG00229. However, these ligands alone did not cause any changes in the sodium or calcium currents.
VEGF-A improves synaptic activity in the dorsal horn
Synaptic activity within the lumbar dorsal horn was found to be increased in the presence of VEGF-A, not in terms of the amplitude of the excitatory postsynaptic current, but in its frequency, which increased by almost fourfold. The magnitude of this increase was reduced by 50% and 57% by protein spike and EG00229. This suggests that these molecules have a presynaptic action and antagonize pain signaling in this pathway.
In a rat model, administration of spike protein or EG00229 was able to completely inhibit VEGF-A signaling in chronic neuropathic pain, thus increasing the pain threshold after injury.
In fact, according to researcher Rajesh Khanna, “The spike protein completely reversed VEGF-induced pain signaling. It didn’t matter if we used very high peak doses or extremely low doses.. “
Transcendence
The study shows that the activity of VEGF-A, a chemical that sensitizes the pain pathway and leads to pain, is inhibited by the spike protein as well as the NRP-1 inhibitor EG00229. Experimental results demonstrate that the SARS-CoV-2 spike protein effectively inhibits pain signaling in the VEGF-A / NRP-1 pathway. In chronic neuropathic pain, spike protein blocked VEGF-A-induced increases in sodium and calcium current densities, reduced spontaneous discharge in DRG neurons, synaptic transmission in lumbar dorsal spinal neurons, and pain due to to mechanical or thermal stimulation after injury.
In patients with COVID-19, the observed high levels of VEGF-A would be expected to be associated with increased pain via the NRP-1 pathway. These results suggest that the spike protein usurps the NRP-1 binding domain typically occupied by VEGF-A, thus reducing pain detected by this pathway.
Said Michael D. Dake, Senior Vice President of Health Sciences at the University of Arizona, “This research raises the possibility that pain, as an early symptom of COVID-19, may be reduced by the SARS-CoV-2 spike protein, as it silences the body’s pain signaling pathways.. “
Khanna explains: “Perhaps the reason for the relentless spread of COVID-19 is that, in the early stages, you are walking well because your pain has been suppressed.. “The researchers plan to continue working on neuropilin as an early spread mechanism of COVID-19.
Second, it is conceivable that the spike protein could serve as the basis for a family of novel pain relief molecules that act through inhibition of NRP-1. However, alternative fragments of the spike protein or other viral proteins may promote pain, and this should be explored in future studies. The sequence of molecular events that occur after VEGF-A / NRP-1 binding also remains to be elucidated.
The NRP-1 MNRP1685A antibody is in clinical trials. The latter prevents the binding of NRP-1 by VEGF-A, but associated neuropathy has been observed. This could be due to inhibition of the alternative splicing isoform VEGF-A165b, which is neuroprotective rather than analgesic.
Therefore, the current study provides a rationale to examine the effect of targeted inhibition of the pronociceptive signaling axis of VEGF-A / NRP-1 rather than broad inhibition of VEGF-A as with the therapeutic monoclonal antibody against cancer. bevacizumab.
Khanna says: “We are advancing the design of small molecules against neuropilin, in particular natural compounds, which could be important for pain relief..
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