Ebola is extremely deadly - deadly things are bad, we want to either treat, or eradicate Ebola. However, one of the reasons why we haven't all died from Ebola is the fact that it's so deadly. Deadly viruses don't reproduce and spread as efficiently as less deadly viruses. There are a few reasons for this, but one reason is that with Ebola you know you're sick, you can't physically move around, and you can't really shed virus before you're symptomatic.
If we treat Ebola to the point of it being attenuated, but not eradicated, could we wind up in a situation where it actually spreads more easily because of the treatment? People might feel on the mend, but still be shedding virus, and go out to public places and spread the disease.
Note: I'm not saying this for sure would happen, and that it's a reason not to treat Ebola, I'm just wondering out loud if that would be a factor.
As long as the virus is either very deadly XOR treated in a quarantined environment, not much changes for widespread infection. Part of the way deadly viruses limit their own spread is by informing our own active countermeasures.
EDIT:
NIH says that some of these vaccines have 97-100% effectiveness in certain aspects of slowing the spread of Zaire ebolavirus, meaning that it's not the effective death sentence it was in 2014, at least not for the vaccinated. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659338/
That’s really interesting to use ubiquitin for replication since “ubiquitinylation” (tagging proteins with the same) is a common signal for protein destruction. Conceptually (didn’t dive into the primary source but am molec nerd), it’s like reprogramming the delete key into a copy button. Fascinating.
There's actually not that much in there about the mechanism, still in the observation stage.
>Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay.
They did a good job showing that Ub is necessary for wild-type polymerase activity, and they did a good job of modeling the interactions and structure-function relationship, which is good from a drug-design perspective. But they didn't really go into why, which is the interesting question from a strategic point-of-view.
>we found that unanchored K48-linked polyUb regulates the antiviral response by promoting IKKε activation to stimulate IFN-I responses [34], and K63-linked polyUb chains can promote RIG-I activation [31,33,53–55], and TAK1 activation [35,56,57]. On the other hand, viruses have been shown to utilize both unanchored Ub and covalent ubiquitination to replicate. In relation to unanchored Ub, Influenza viruses contain unanchored Ub in infectious virions, which can enhance virus replication by promoting uncoating via histone deacetylase 6 (HDAC6) [58,59], and other viruses may use similar mechanisms [60]
This seems counterintuitive. The ubiquitinylation is activating inflammatory response, but then why would viral polymerase activity require ubiquitin? You'd think the viruses would evolve away from inflammatory response, not towards.
> The ubiquitinylation is activating inflammatory response, but then why would viral polymerase activity require ubiquitin? You'd think the viruses would evolve away from inflammatory response, not towards.
tl;dr - Basically, this seems like it's a mechanism that is akin to the invading virus getting read access (if not root) on the cells security system, to better respond to its environment.
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It's been awhile since my biochem, but here are my thoughts tumbling around (not guaranteed correct):
- this might be like an invader noticing that the cells defences are increasing, and being able to scale it's activity with the cellular counter-response, done via activation of Ub.
- polyub chains attached to a protein are like a stronger signal for deletion. the more anchored polyUb chains, the more likely/quickly something will be tagged for removal.
- unanchored polyUb chains (that have been cut off destroyed proteins) would be a signal that a severe immune response is underway. for these free/unanchored polyUb chains to be an activator of something viral, it's the virus having a way to know when things are getting serious in the cell.
- unanchored ub might be a byproduct of a tagging. it may be active form, free-floating. High unachored ub might be product of higher transcription during stresss/inflamatory response
it would be great if the news source actually said, in human terms, what the discovery was. I'm looking at the paper and I don't understand the nuance.
I know science reporting is hard, but this news piece could be copied and pasted to virtually any other paper with minimal effort and still have the same level of insight.
> In this study, we demonstrated that the VP35 protein of EBOV interacts non-covalently with unanchored K63-linked polyUb chains. This interaction between Ub and VP35 promotes viral polymerase activity leading to optimal virus replication.
> Using a pharmacological approach to block Ub-VP35 interactions, we showed that these interactions are relevant in promoting polymerase activity and replication of infectious EBOV. However, loss of Ub interaction with VP35 did not show a perfect correlation with the reduced polymerase activity and virus replication.
In short, it seems as though the ebola VP35 protein interacts with certain types of ubiquitin proteins (a protein found in most of our cells) and that blocking this interaction with drugs led to reduced but not zero replication. I figure their line of reasoning is to determine which interactions between proteins are crucial and then design some drugs with the help of computation models to severely reduce replication -- so far, no real success but a step in the right direction.
“New theory of Ebola replication “ would be more accurate. The idea of Ebola evolving a new and novel way to replicate in humans is not a pleasant thing to ponder lol.
These days, I end up wondering whether this kind of bait and switch title writing has worked its way up to food chain into professional journals. Enshitification
indeed.
Yeah, but even that title teases the possibility that there is a novel, and not merely newly discovered, replication mechanism. I mean, it’s better, and falls into the “surely they don’t mean that…” category, but still.
Interesting but based on modeling, not experimental results insofar as I can tell from the PLoS paper the news article refers to (1). So take it with a big grain of salt.
Ebola is extremely deadly - deadly things are bad, we want to either treat, or eradicate Ebola. However, one of the reasons why we haven't all died from Ebola is the fact that it's so deadly. Deadly viruses don't reproduce and spread as efficiently as less deadly viruses. There are a few reasons for this, but one reason is that with Ebola you know you're sick, you can't physically move around, and you can't really shed virus before you're symptomatic.
If we treat Ebola to the point of it being attenuated, but not eradicated, could we wind up in a situation where it actually spreads more easily because of the treatment? People might feel on the mend, but still be shedding virus, and go out to public places and spread the disease.
Note: I'm not saying this for sure would happen, and that it's a reason not to treat Ebola, I'm just wondering out loud if that would be a factor.