COVID Transmissions for 6-23-2021
An exploration of how SARS-CoV-2 exploits cells
Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.
It has been 583 days since the first documented human case of COVID-19. In 583 (approximately), a smallpox epidemic began to spread from China to Japan and Korea. There are thousands of years of human history where we were at the complete mercy of viruses. We’ve come a long way, and smallpox is now a matter of history because of vaccines.
Today I’m going to take you into the world of basic science, to look closely at how SARS-CoV-2 exploits known host processes to its own advantage. I also update on the US vaccination situation and the alarming spread of the Delta (B.1.617.2) variant. And then there’s a story about just how much all the SARS-CoV-2 in the world right now might weigh—it’s possibly less than a common sledgehammer.
Bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
70% of US adults over 30 now have received at least one vaccine dose; younger ages, not so much
Yesterday, the White House announced that 70% of US adults over the age of 30 have received at least one vaccine dose at this point. CIDRAP has the story: https://www.cidrap.umn.edu/news-perspective/2021/06/white-house-70-adults-30-and-have-1-dose-covid-vaccine
The problem is that overall, only about 53% of the total US population has received one dose, and only about 45% are fully vaccinated. That’s simply not enough, and the Delta (B.1.617.2) variant has been accelerating its rise to dominance in the US. Last issue, I was concerned about how this variant had gone quickly from 6% to 10% of infections. In the intervening time, I have now learned it has leapt to being responsible for 31% of infections in the US. That is a far more rapid rise than anyone expected. This dangerous variant is very much here, and we need to be vaccinated to stop it.
This story can and will play out in other countries, too, so don’t think that my US focus localizes the danger to my own country, either. Beware what is happening, because it is a serious threat.
Basic science: manipulating the unfolded protein response to control SARS-CoV-2 replication
One of the most interesting things about viruses is that they can be excellent tools for teaching us how cells work. As consummate exploiters of cellular processes, viruses can be counted on to find every loophole in cellular functions in some way or another. When a new molecular mechanism in living organisms is discovered, often it is not long before a virologist finds some virus that exploits that mechanism. Sometimes, even, entirely new molecular mechanisms are discovered only because viruses turn out to exploit them.
For this reason, every new virus offers opportunities to expand our understanding of basic science. This can have a lot of payoff in terms of future impacts on human health, but is also fundamentally interesting for the advancement of human knowledge.
SARS-CoV-2 is, apparently, no exception. In a recent paper, scientists studying the unfolded protein response—I’ll explain that in a moment—were able to demonstrate that the virus exploits this cellular process, and in fact turn that discovery to an experimental system where they could hamper virus replication in human lung cells. Paper here: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009644
The unfolded protein response (UPR) is a set of pathways that are meant to help cells manage high stress on a major center of protein production, called the endoplasmic reticulum (ER). The ER was named at a time when “approachability” was not a huge priority for scientists—apparently—but its name basically means “network in the inner layer of the cell.” Which is exactly what it is. It is a membrane-enclosed maze within cells that is involved with manufacture of proteins, among other things.
In a virus infection, the virus exploits the cell’s typical protein production pathways, and this includes using the ER to manufacture many viral components. The large volume of viral protein products made leads to ER stress, and activation of the UPR follows.
The researchers working on this study demonstrated that during coronavirus infections—starting with MHV, a model coronavirus—the UPR is strongly activated. This is interesting, but not especially surprising. They also found that expression of specific SARS-CoV-2 proteins in cells could, on its own, activate the UPR. I would be skeptical of that effect if not for the fact that the researchers went further and performed genuine SARS-CoV-2 infections, demonstrating the same effect. This is an important principle in virology—it is often not enough to just work with virus components, because life has so many moving parts. To confirm results, it is ideal to be able to work directly with the virus itself. You might need to take my word for it, but this Western Blot (an experimental system for measuring protein) shows activation of the UPR in the presence of SARS-CoV-2 infection:
So far, this showed the researchers things that they largely expected from beginning their investigation into the UPR. But when you see something interesting like this, you ask another question: does activation of the UPR make it harder for the virus to replicate?
Now here’s where things get really interesting: the researchers had access to a variety of inhibitors of the UPR, and they explored the effect of those inhibitors on the replication of the two viruses, both MHV and SARS-CoV-2. Tantalizingly, both viruses saw their replication inhibited if the UPR was turned down by outside influences! Instead of getting better at replicating when the UPR is suppressed—something we might have expected from a stress response that normally helps cells survive—the viruses got worse at replicating without the UPR functioning. What we normally think of as a stress response to protein overproduction, and which is expected to slow down protein synthesis, seems to actually be important for these viruses to replicate.
The implication here is that the viruses not only activate the UPR, but they are in fact evolved to exploit that activation to their own ends! This is exactly the kind of thing that viruses surprise you with. It’s not too surprising if you really think about it—a virus needs its host if it is to replicate, so perhaps the UPR is as beneficial to the virus as it is to the cell—but this really could have gone either way. But, as viruses usually do, these have evolved to find a way to use the cell’s response to their presence as an advantage rather than a hindrance.
Now, in my opinion, this is just cool scientifically. We’ve learned something fundamental here about the interaction between coronaviruses and their hosts, here. But it also suggests that, if developed appropriately, drugs capable of shutting down the UPR could potentially serve as antivirals to control coronavirus infections.
The weight of SARS-CoV-2
Researchers at Caltech and Israel’s Weizmann Institute have estimated the total weight of all of the SARS-CoV-2 particles in all the patients in all the world. There are billions of particles, potentially, in every patient. There have been around 180 million total cases throughout the pandemic, and worldwide there are about 410,000 new cases per day. So just in terms of new daily cases, that could be roughly 410 trillion virus particles.
On the other hand, viruses are very small. They are measured in billionths of a meter, and they are made out of fat, protein, and water—not exactly the heaviest things known to humanity.
Taking these and many other factors into consideration, the authors of this new study estimate that all the SARS-CoV-2 particles in the world, combined, might weigh as little as 100 grams and no more than 10 kilograms. The upper end is about the weight of a typical sledgehammer. The lower end is about the weight of a fork or a spoon.
It’s remarkable to think that something weighing no more than a few common hand tools could be enough to bring the world to its knees. I remember the famous story of Archimedes saying that he could lift the world if you gave him a long enough lever. Well, if that lever is made of viruses, apparently it doesn’t need to be very long at all.
Story here: https://www.pnas.org/content/118/25/e2024815118
What am I doing to cope with the pandemic? This:
Buy nothing: new bike
I’m excited to say that using a local Buy Nothing group, I was able to get myself a “new” (it’s from the late 1970s but well-preserved) road bike. It’s an Austro-Daimler SLE, and it’s in pretty good condition:
I’m looking forward to getting this out on the bike paths around NYC over the summer, before whatever happens with weather and viruses in the fall makes it harder to enjoy the world around me.
Carl Fink shared a Nature news story looking into CureVac, and exploring potential explanations for why their vaccine candidate might have failed:
Nature has an article on the CureVac disappointment.
There are vaccinologists who agree with me that the unsubstituted uridine of the CureVac mRNA is a plausible reason, but it isn't the only one.
Here are my thoughts:
Yeah, I don’t think it’s implausible. When I said I don’t “understand” why it would impact things considering that the CureVac vaccine showed an immune response in earlier trials, that doesn’t mean I think it can’t be a factor. It just means that I can’t square the two facts with each other. But at the same time, I can’t square most of the facts in this disappointment with each other. There are obviously some things that we don’t know about immune response to COVID-19. Additionally, we should consider that changes to lockdown conditions and other behavioral factors might also have impacted the CureVac trial.
When it comes specifically to the substitution of pseudouridine in the other vaccines vs the normal uridine in the CureVac option, what’s really confusing is that pseudouridine is supposed to reduce immune responses, not increase them. But for some reason, CureVac doesn’t seem to have done the job, even without this modulating substitution. I can speculate as to how that may be related. Perhaps CureVac has a kinetic problem—low RNA dose combined with too-strong activation of an innate immune response. One thing that innate immune responses can do is activate host cells’ RNAse L, which rapidly degrades every RNA in the cell. Maybe a low dose of RNA combined with a strong activator of innate responses degrades the CureVac RNA too quickly for it to be effective.
But if that’s true, where did the antibodies seen in earlier trials come from? Very confusing. The article you linked does note that those levels were lower than what we see with the other mRNA vaccines, but still around as high as seen with natural SARS-CoV-2 infection. In that same section, they suppose as I did before that dose was a big factor here. But it really is too early to know. I hope we get more detailed information soon.
Reader Sam had a comment on President Biden’s concern over the Delta variant in young people:
Perhaps what Biden was trying to say is that Delta likely causes more severe disease in general, and so may inflict more severe disease on young people in absolute terms, even if they're still, ceteris paribus, relatively more protected from it than older people.
My response:
Very possible! Even if it causes equally severe disease, though, its enhanced contagiousness might make it even more dangerous on its own, at a population level. That will increase its likelihood of getting to those young people who are most vulnerable. I’m not sure which it is, but I can see a number of scenarios where it could be pretty dangerous.
You might have some questions or comments! Send them in. As several folks have figured out, you can also email me if you have a comment that you don’t want to share with the whole group.
Join the conversation, and what you say will impact what I talk about in the next issue.
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See you all next time. And don’t forget to share the newsletter if you liked it.
Always,
JS
Of 18,000 deaths from COVID-19 in May, 150 were among the vaccinated.
Will this convince antivaxers?
https://www.snopes.com/ap/2021/06/24/nearly-all-covid-deaths-in-us-are-now-among-unvaccinated/