BREAKING! COVID-19 Research: Sodium Channels Could Be Affected As Coronavirus Spike Protein Has Similar Sequence To Human Epithelial Sodium Channel
: Researchers from a biomedical cum AI company based in Cambridge, Massachusetts have discovered that the SARS-CoV-2 spike protein’s furin cleavage site is identical to a sequence in the human epithelial sodium channel, which likewise must be cut by furin in order to be activated. The researchers propose that the new coronavirus may be competing with the sodium channel for furin, and possibly disrupting its function, but that remains to be demonstrated.
The researchers found that eight amino acids are identical to part of the human epithelial sodium channel, leading researchers to suspect the SARS-CoV-2 coronavirus might interfere with the channel’s function.
This discovery could also help explain why COVID-19 patients sometimes end up with large amounts of fluid in the lungs.
The research findings were published in the journal eLife and have been peer-reviewed. https://elifesciences.org/articles/58603
It was determined earlier this year that there is a cleavage site in the SARS-CoV-2 spike protein for furin, a human protease, and that the spike protein is split into two subunits at that spot. This cleavage has been implicated in helping break the virus open so it can enter human cells. https://www.sciencedirect.com/science/article/pii/S0092867420302622
The breakthrough came about when scientists at nference, a biomedical cum artificial intelligence company, started looking to see whether are there any sequences of amino acids in SARS-CoV-2 proteins that seemed unique or unusual.
Interestingly one that stuck out, says Dr Venky Soundararajan, nference’s chief scientific officer, was a stretch of four amino acids present in the spike protein of 10,956 of 10,967 SARS-CoV-2 isolates from around the world, but not in the protein’s sequence in related coronaviruses, such as SARS-CoV or varieties that infect bats or pangolins.
Few other researchers had reported in February and April that this insertion forms a cleavage site for the human protease furin, which is thought to sever the two subunits of the spike protein to facilitate entry into human cells. https://www.sciencedirect.com/science/article/pii/S0166354220300528
Dr Soundararajan and the rest of the researchers strengthened this hypothesis when they determined that the furin cleavage site is identical to a proven furin cleavage sequence in the alpha subunit of the human epithelial sodium channel, which plays a role in managing the balance of salt and fluid in many of the body’s cells. This site is essential in the process of assembling the channel’s subunits into a functional whole capable of regulating sodium levels in a cell.
The study team then turned to a platform they developed, which uses a database of single-cell RNA expression data from 65 previously published human and mouse studies, to look into gene expression of the sodium channel and other human genes known to be involved in SARS-Co
The team found that expression of the epithelial sodium channel’s gene overlaps with that of the gene for furin and for the primary SARS-CoV-2 receptor, ACE2, in the cell types most affected by the virus.
Significantly, the coupling of ACE2, the epithelial sodium channel, and furin in the epithelial cells of the nasal cavity, the respiratory tract, and the gut supports the idea that those regions are the initial hubs of infection in the human body, Dr Soundararajan says.
Some researchers warn against making assumptions about ACE2 abundance based on transcript levels. “We have to always be a little careful going from gene expression to what’s assembled on the membrane.” they say.
Hence, based on this RNA co-expression, the researchers hypothesize that during a SARS-CoV-2 infection, the viral spike protein might compete with the human sodium channel for furin cleavage. If this competition disrupts the activation of the sodium channel, it could become dysregulated, which could interfere with its role in regulating fluid balance. This could explain why COVID-19 patients sometimes end up with large amounts of fluid in the lungs.
Thailand Medical News however warns that it should be noted that the study is all computationally based with no wet experiments.
There is no proof that this sodium channel is downregulated during viral infection. But if furin has a higher affinity for the virus and there is a high viral load in the same region where this sodium channel is expressed, “there is potential there that you’d have less processing of that alpha subunit of the sodium channel and this potentially could also affect sodium channel function locally.”
Dr Dario Ghersi, a computational biologist at the University of Nebraska Omaha who did not participate in the study commented, “Most computational analysis requires some experimental validation. That this recognition site is present in the majority of SARS-CoV-2 isolates implies that it is important to the virus, meaning the sequence could be of interest for vaccine and therapeutic development. What they found seems pretty solid to me”.
The research findings has triggered other study teams to explore this hypothesis further.
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