So, here's another great paper out today from my friend and colleague @DrSimonAnthony.

It will be of particular interest to those pondering possible SARS-CoV-2 origins, and viral evolution enthusiasts in general.

Brace yourself: it's about how different sarbecoviruses use ACE2.
In short: Dr. Anthony and his PREDICT colleagues found 3 isolates of a novel sarbecovirus (SARS-like betacoronavirus) in bats...from Uganda and Rwanda. Hey, that's nowhere near China, so what does that have to do with SARS-CoV-2?
A lot, actually. Sarbecoviruses are not exclusive to China or East Asia. That's where they've been studied most extensively, but they aren't restricted to that part of the world. Here's how these viruses and host bat species relate to each other and where they were discovered.
This phylogenetic tree was constructed using the RNA-dependent RNA polymerase (RdRp), the gene encoding the enzyme that copies the virus genome during replication. But hey that's not involved in entry, so what does that have to do with infection? TELL US ABOUT THE SPIKE PROTEIN!
Even among closely related viruses found in China, there are a whole bunch of them that can't bind human ACE2, including viruses that seem to be closely related based on their RdRp sequence.
ACE2 binding is determined by part of the spike protein that binds ACE2 and allows it to enter a cell, the receptor-binding domain (RBD). If the RBD is incompatible with human ACE2, that virus won't be able to enter a human cell and therefore can't infect humans.
So they constructed a phylogenetic tree based on the RBD and compared it to the tree based on the RdRp. Turns out some of these viruses are not as closely related based on the RBD sequences and can't bind ACE2. How could that be?
Take a look at SARS-CoV classic and SARS-CoV-2. They are very distantly related based on the RdRp, but both are obviously capable of binding human ACE2. This would suggest that these different parts of the genomes are evolving at different rates. How does that happen?

There are multiple sarbecoviruses viruses circulating in bats that live in the same geographical area. For SARS-CoV and SARS-CoV-2, that's Yunnan province. If you have two distinct viruses infecting the same bat, they can swap parts of their genomes.
This leads to new recombinant viruses that can gain or lose the ability to bind human ACE2. Those viruses will then continue to evolve and adapt as they continue circulating in bats. If this happens over and over, the results can be unpredictable.
Here's a proposed timeline for which all this recombination could have occurred.

Lineage 1=SARS classic.
Lineage 5=SARS-CoV-2.

SARS classic actually picked up its ability to bind ACE2 from recombination with one of SARS-CoV-2's lineage 5 ancestors.
So what does this have to do with those African sarbecoviruses I mentioned? They don't bind ACE2, as shown here. (Note: this is not a GASP gain-of-function study since this is a VSV pseudovirus system). In these experiments, SARS-CoV-2 spike binds ACE2, the African CoVs do not.
Since the viruses from Rwanda and Uganda don't overlap geographically with the sarbecoviruses from Yunnan province there's no opportunity for them to acquire the ability to bind ACE2 through recombination.
But studying those novel sarbecoviruses provided insight into how certain traits (like RBDs that bind ACE2) emerge, and also suggests that SARS-CoV-2 didn't come from Wuhan. It came from the same place that SARS-CoV classic did: somewhere in southern China.
It shows how important it is to study the natural history of these viruses, so we can better understand pathways of zoonotic emergence (and if you're interested in working on this yourself, @DrSimonAnthony is hiring postdocs! Join him in sunny California at @ucdavisvetmed!) the risk of getting a bunch of lab leakists in my replies, it provides a compelling pathway supporting natural zoonotic origins of SARS-CoV-2. It suggests that SARS-CoV-2 wouldn't need to be passaged, cloned, or studied in an accident-prone lab to infect humans.
The ancestral lineage of SARS-CoV-2 has long had the ability to bind human ACE2. It's very plausible that someone encountered an immediate ACE2-binding progenitor of SARS-CoV-2 in nature, became infected, & the virus adapted to a human host by spreading silently through humans.
Of course like all hypotheses, that could be wrong. It needs to be tested and supported with more evidence. But this paper reinforces the importance of continuing to sample and study these viruses and their natural history and evolution.
These natural history studies can help us make sense of the origins of this pandemic, and just might help prevent the next one.

Great work, @DrSimonAnthony, @FViromics, @bahanbug, @ChandranLab, @JonnaMazet, and all the authors who aren't on Twitter or whose handles I don't know!

• • •

Missing some Tweet in this thread? You can try to force a refresh

Keep Current with Dr. Angela Rasmussen

Dr. Angela Rasmussen Profile picture

Stay in touch and get notified when new unrolls are available from this author!

Read all threads

This Thread may be Removed Anytime!


Twitter may remove this content at anytime! Save it as PDF for later use!

Try unrolling a thread yourself!

how to unroll video
  1. Follow @ThreadReaderApp to mention us!

  2. From a Twitter thread mention us with a keyword "unroll"
@threadreaderapp unroll

Practice here first or read more on our help page!

More from @angie_rasmussen

19 Mar
No, you can’t. Kids being lower risk does not mean “same as an already vaccinated grandparent.”

I value other perspectives, like economics, in vaccine discussions. All are stakeholders in public health. But have the humility to know when you’ve hit the limits of your expertise.
This is insufficient. The problem wasn't just the headline. The problem is that two of the fundamental arguments are wrong.

1. Risk of infection is just as relevant as risk of disease.

2. Vaccinating only adults won't get us to herd immunity by summer.
And I should add there's another risk that wasn't addressed at all: the vaccines are not 100% effective (though they are very good). Failing to mitigate transmission risk by relying on flawed risk assessments still presents a danger, especially to more vulnerable adults.
Read 4 tweets
12 Mar
The sequences from the Ebola virus outbreak in Guinea were posted on virological, and they are, to put it mildly, absolutely stunning.

The sequences are only 12-13 nucleotides different from those circulating in the 2014-2016 epidemic.…
This suggests that this new outbreak resulted from transmission from a persistently infected survivor of the prior epidemic, which is bad for a whole host of reasons, including the further stigmatization of Ebola virus disease survivors.…
This is also genuinely shocking to me scientifically.

Based on the known mutation rate of EBOV/Makona, we'd expect viruses that have been replicating for 5-7 years, even at low levels, to have many more mutations. Like hundreds. These have 12.…
Read 8 tweets
11 Mar
Good grief. This isn’t even a study—it’s a preprint of a perspective piece advancing an untested hypothesis (pork shortages led people to seek other meat sources). You can poke holes in this without much effort.
For example, do the authors really think that ASF-induced shortages of farmed pork led people to start sourcing wildlife to replace it? It would take many metric shit-tons of bats and civets to replace the lost pork.
Why wouldn’t most shoppers just use a more readily available meat like duck?

I know when pork chops are sold out, I immediately start thinking about sourcing some rhinolophid bat meat to replace it. Then I realize that’s dumb and just grab a chicken or whatever instead.
Read 9 tweets
10 Mar
I'm writing about this (among other knowledge gaps still to be filled with regard to SARS-CoV-2) and Dr. Goldstein is right: I've been working on host responses to the big bad beta-CoVs since 2012, but haven't given much thought about tissue tropism of the other hCoVs...
This has led me to think about the relevance of fecal shedding for SARS-CoV-2 to transmission. The key to understanding SARS-CoV-2 transmission is that it's situational, even with more dominant modes (inhalation, direct contact) of transmission.
Dating back to SARS classic in 2003 & now with SARS-CoV-2, transmission via fecal bioaerosols is thought to occur when specific conditions occur with a building's plumbing. Despite lots of 🚨🚽🦠⛲️💩☣️-type tweets about it, people aren't getting COVID every time a toilet flushes.
Read 22 tweets
3 Mar
It has come to my attention that noted anti-vaccine zealot Robert F. Kennedy Jr. is releasing a film tomorrow targeting the Black community with some appalling misinformation.

It is not just filled with falsehoods. Despite claiming to be anti-racist, it is racist as hell
Medical racism absolutely exists, and underlies the disproportionate impact on the COVID-19 pandemic on the Black community. But correcting those disparities by claiming vaccines contribute to medical racism?

That's much, much worse.
You know what the result of discouraging Black people from getting the COVID-19 vaccine will be?

More preventable deaths in the Black community.

Race-based targeting with the goal of more Black people dying as a result?

It's morally bankrupt and outright racist.
Read 5 tweets
2 Mar
This position is very frustrating. It's both inconsistent with Church teachings and based on an inaccurate understanding of vaccine development.

1. The Vatican has reiterated that it is morally acceptable to use vaccines developed with HEK293 cells.…
2. HEK293 cells were taken from a single legally aborted fetus in the Netherlands nearly 50 years ago. Fetal tissue is not continually harvested for use in vaccine development. Virtually every medical/therapeutic/vaccine on the market used this cell line at some point.
3. Moderna and Pfizer also used HEK293 cells to perform confirmatory testing of their vaccines.

4. None of the vaccines contain actual fetal tissue.

5. If you are "pro-life," presumably you also object to millions dying from a preventable infectious disease as well as abortion.
Read 4 tweets

Did Thread Reader help you today?

Support us! We are indie developers!

This site is made by just two indie developers on a laptop doing marketing, support and development! Read more about the story.

Become a Premium Member ($3/month or $30/year) and get exclusive features!

Become Premium

Too expensive? Make a small donation by buying us coffee ($5) or help with server cost ($10)

Donate via Paypal Become our Patreon

Thank you for your support!

Follow Us on Twitter!