2019-nCoV may contain a gain-of-function for efficient spreading
sciencedirect.com
sciencedirect.com
I am completely baffled to the meaning of this given the scientific nomenclature used, but I would really like to know what it means and why it is front page HN.
What I imagine it means is that the red things on this picture
https://www.cdc.gov/homepage/images/banner/covid-19-1330px.j...
have some sort of indentation, or cleavage, that makes them either more or less dangerous.
Am I close? Can someone who understands explain for the layman?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996883/
Not sure that's what the other intended though, would appreciate someone with technical understanding interpreting.
The gain of function mutation is a cleavage site, which means that a new protein can be created, which could have some new activity. This cleavage site looks like a Furin cleavage site: Furin is associated with transporting proteins inside a cell, and thus with infection. So a drug targeting the Furin pathway may block the effect of this gain of function mutation, and make COVID-19 less infections to those taking it.
Some background: viruses primarily contain the genetic material and a protein coat. The Spike (S) protein is one of the proteins in the coat, and plays a role in whether an infection will take root.
From the paper:
> we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the other SARS-like CoVs
Furin is a protease that is present in healthy humans. Some proteins aren't "active" until they're cut (cleaved) at specific sites along their sequence, so furin's "job" is to cleave these proteins - activating them. Notably, furin is highly expressed in the lungs.
2019-nCoV apparently has a "furin-like site" in its Spike protein - a sequence that furin can bind to and cleave. Notably, furin is the protease that cleaves one of the proteins in the protein coat of HIV, which then allows for viral replication [1]. The authors therefore hypothesize that this mutation which creates the furin-like cleavage site accounts for some of the pathogenicity of 2019-nCoV. They further hypothesize that furin inhibitors may be effective agents in combating the virus (which have shown some promise in combating other viruses, tumours, etc.).
Disclaimer: not a virologist, just a computational biologist with a bit of interest in structural biology. Also, the authors emphasize that further experimentation needs to be done to validate this claim.
[1] doi:10.1038/360358a0
> This furin-like cleavage site...may provide a gain-of-function to the 2019-nCoV for efficient spreading in the human population compared to other lineage b beta- coronaviruses.
Can somebody who understands this please elaborate on the implications?
I’m thinking what the heck is a Gainof Function?
For a virus I suppose this would be function in reproduction.
[1] https://journals.sagepub.com/doi/abs/10.1177/030631271666642...
Where this new shape came from, they do not know. But since viruses tend to mutate a lot and integrate RNA snippets floating around in their host's blood stream, it is likely that they picked it up from some other virus simultaneously infecting the same individual.
In short, the new nCoV seems to be so contagious because it merged in a new feature from a different virus species.
The implication is that by specifically blocking this thing that nCov has but older Cov do not have, one might be able to drastically reduce its contagiousness.
> ...must be cleaved by furin or furin-like proteases to become fully functional. Anthrax toxin, pseudomonas exotoxin, and papillomaviruses must be processed by furin during their initial entry into host cells.
From the sound of this:
- the site on the virus gets cleaved - Furin enables the cleaving - Furin exists in hosts cells
What I think I understand is, the cleaving makes it easier for the virus to reproduce inside the cell?
edit: turns out I have no idea how to format things on HN
Here is a review article from 2019 on furin. Apparently several viruses use this "trick" as part of their entry mechanism.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682551/
(I have some biology studies from long ago, I am not professional in molecular biology.)
there is a protien [protease] in the extracellular space of your tissues that cleaves other protiens these are called Furins.
Furins activate enzymes where they are needed by cleaving [cutting away all the shipping wrap].
The S protien of the nCoV SARS 2 virus has a cleavage site that is cut by the furin class of protiens.
this seems to be a modification as the SARS CoV does not have this cleavage site as far as can be seen for the time.
so what does this do?
the S protien is specific to a binding site [ACE2] and that will be found in high prevalence in the lungs, but is found elsewhere. the corona virus does not seem to shed through the skin but through mucous and sputum so the virus that is efficient at lung infection will win when this is its transmission mode.
if the virus doesnt make it to the lungs it is in a less than optimal place for survival compared to the lungs.
so the virus has a specific tag recognition sequence to find ACE2 and stick.
this is where the Furin comes in. The S protien is in shipping state until it reaches the lungs and is cleaved by Furin, this is when the S protien become S1; S2.
the S1 stays bound to ACE2, the S2 does some work and wrenches the cell membrane open then inserts its nucleocapsid---this is now an infection.
the exact details are not entirely worked out such as is there an absolute requirement for S binding or S cleavage in any particular order. and does anything else participate in the process.
the authour suggests some correlation of furin cleavage sites with increased pathogenicity [potential to cause disease] based on observations of other unrelated virus having a newly acquired cleavage site correlated with increased proclivity to cause a disease process in humans.
there may be some undercurrent regarding these molecular feature as a general theme in biology, however there is not a firm scientific consensus that this is the case.
the articel referenced is a preproof meaning it is close to being accepted for publishing so it isnt science yet.
[PDF] here :
Most of us here are not medical or epidemiological experts at all, and most of the comments here are just people asking for an layman's explanation of this paper. Trying to ascribe meaning to highly technical results seems futile (at best) or irresponsible (at worst).
There is no harm in having smart people reading breakthrough literature in other fields. Even if we don't understand every detail, often with enough experience in other fields you can still get the gist and there's always opportunity for cross-pollination.
>Trying to ascribe meaning to highly technical results seems futile (at best) or irresponsible (at worst).
I'd like to point out that this is primarily how grad school on the cutting edge works. You pick a subject and start reading papers until piece by piece things start to make sense. Frequently people do so by jumping into a graduate topic that can be quite different from their undergrad, and this is still a valid way to learn for a subset of the population.
Frankly given the gravity of the pandemic I don't think any published article is inappropriate for HN right now.
"On-Topic: Anything that good hackers would find interesting. That includes more than hacking and startups. If you had to reduce it to a sentence, the answer might be: anything that gratifies one's intellectual curiosity."
also:
"Please don't complain that a submission is inappropriate. If a story is spam or off-topic, flag it. Don't feed egregious comments by replying; flag them instead. If you flag, please don't also comment that you did."
Here is my non-doctor take in non-doctor words - and possibly wrong. I've tried to source where possible.
* Betacoronaviruses have four lineages (A-D). This is actually sourced. [0]
* 2019-nCov is lineage B, which is the same as original SARS. MERS is lineage C. This is sourced as well. [0]
* 2019-nCov has a "furin-like" cleavage site, which other lineage B betacoronaviruses do not. Sourced as the article for this thread.
* I believe a cleavage site plays a role in how a virus binds to and enters a cell. Personal interpretation - could be wrong.
* Based on Wikipedia, "Furin". I believe this means either (1) that the 2019-nCov has a cleavage site that requires modification to activate or (2) 2019-nCov has a cleavage site that resembles the human FURIN gene. I'm clearly out of my territory on this statement so fact check it yourself.
* People developing treatments should consider this "furin-like" cleavage site for therapies as they "may" have implications on the virus lifecycle. From the source article.
[0]https://www.nature.com/articles/s41564-020-0688-y
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My personal take is identifying viruses treatments is a bit like writing a very complex pattern match in software. It needs to be specific enough to not kill good cells, but general enough handle uniqueness among individual virus cells.
This articles seems to be identifying a unique pattern within 2019-nCov that people developing treatments should consider this. It may also be suggesting that the "unique" factor is hidden in some way.
----
What that means for any of us on Hacker News? I don't know.
2019-nCov may contain a mutation for efficient spreading
1 - Gain-of-function mutation: A mutation that confers new or enhanced activity on a protein.
But anything that does get killed by our immune system is kind of on the clock and needs to spread relatively quickly.
"This furin-like cleavage site, is supposed to be cleaved during virus egress (Mille and Whittaker, 2014) for S-protein “priming” and may provide a gain-of-function to the 2019-nCoV for efficient spreading in the human population compared to other lineage b betacoronaviruses. This possibly illustrates a convergent evolution pathway between unrelated CoVs. "
Here's what gain of function means in a biological context. When you have a mutation occur to a protein coding gene, one of two overall things can happen - nothing or something. Genetic code has some built in redundancies that mean that you can swap out some DNA base pairs and end up with the same protein in the end. If something happens, there's broadly two types of thing that could happen to the resulting protein. You could have a loss of function - where the gene basically breaks, or a gain of funciton - where the gene either works better or gains the ability to do something new. (Of course "nothing much happens" is also an option here if the new protein is similar to the old one).
One important context this comes up in is cancer. You have genes in your genome that are actively stopping cancer from forming and spreading (tumor suppressor genes) as well as genes that would, if allowed to work unrestrained ( think a gene that signals for cell growth) would cause cancer (proto-oncogenes). A gain of function mutation in a proto-oncogene turns it into a cancer-driving oncogene, and a loss of function gene in tumor suppressors opens the door for oncogenes to do their work unrestrained.
In the context of this virus, the authors identified a mutation in the spike protein (one of the important proteins in the virus involved in a lot of its biological processes including infeting a cell) that is not present in it's evolutionary cousins. Basically, this particular coronavirus spreading right now, even though it is very closely related to previous coronaviruses, seems to ahve this one bit in its genetic code that is starkly different, suggesting that this strain/subspecies/species picked up this mutation recently. Now, seeing that the new coronavirus has this genetic feature could indicate one of two things. Either, it's just an artifact of the founders effect where the small population of viruses that jumped from that bat or snake or pangolin to a human would have genetic differences just by chance, and because that small population got blown up to a huge population, the mutation is just along for a ride. Or, it could be a factor in allowing this species to succeed in the first place.
OK, now to the actual mutation. The authors argue the latter - that this mutation might be important in the virus finding the success that it did. They basically found that this mutation leads to that part of the spike protein being more easily able to be cleaved (cut) by the protein Furin. This cleaving of the protein would better prime the virus to be able to infect cells and allow it to infect humans more specifically, and they note that Furin is highly expressed in the lungs as well. They note that a lot of experimental work has to be done to validate this, so it looks like they identified this computationally/with sequence analysis, but it could prove an important lead in terms of figuring out why is this coronavirus more infective than others in humans and provide a new therapeutic target for tackling this strain of the virus.
So to summarize, there are many species of coronaviruses out there, including many related to this particular strain. In this strain, however, there's a mutation that seems to be unique to it. THis mutaiton is a "gain of function" mutation, meaning that it allows the spike protein the mutation is in to work better or get new functionalities compared to SARS/MERS viruses. (If it was a loss of function mutation - then you could reason that you would get something less infective since the protein wouldn't be able to work). The hypothesized mechanism of gain of function in volves of protein highly expressed in the lung that could help explain why it's so much more contagious than previous coronaviruses and also provide a target for therapeutic intervention. More experimental work needs to be done to validate it.
I hope that was clear and noot too detailed or too high level - please let me know if any aspect was confusing and if that was a helpful explanation.
I'll stick to my discipline, fungal infections, in future!
> Strikingly, the 2019-nCoV S-protein sequence contains 12 additional nucleotides upstream of the single Arg↓ cleavage site 1 (Fig. 1, Fig. 2) leading to a predictively solvent-exposed PRRAR↓SV sequence, which corresponds to a canonical furin-like cleavage site (Braun and Sauter, 2019; Izaguirre, 2019; Seidah and Prat, 2012). This furin-like cleavage site, is supposed to be cleaved during virus egress (Mille and Whittaker, 2014) for S-protein “priming” and may provide a gain-of-function to the 2019-nCoV for efficient spreading in the human population compared to other lineage b betacoronaviruses. This possibly illustrates a convergent evolution pathway between unrelated CoVs.