Thread by @MichaelWorobey

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Wow. Huge development. SARS-related CoVs in bats in Europe just one mutation away from a polybasic furin cleavage at S1/S2.

And these very bat samples might contain low-frequency variants *with* functional FCS.
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biorxiv.org/content/10.110…

This is work led by @c_drosten and Jan Felix Drexler, and congrats to first author @ana_lenina, and the other co-authors.

Quick background: SARS-CoV-2 is unique among SARSr-CoVs in having a short stretch of basic amino acids in its Spike protein, the FCS,
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This motif allows SC2 to infect lung cells and is likely a key to this virus's high transmissability. It is the secret sauce that allowed it to become a pandemic pathogen (along with other features like Spike's ability to bind well to proteins on human cells)
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In the figure of the preprint, you can see SC2's "RRAR" FCS, along with similar motifs in SARSr-CoVs from Europe, Africa and Asia.
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A polybasic FCS in a bat may provide no advantage, since the virus infects bats' guts not, lungs. But should a bat virus with an FCS, or something close to it, find its way into a mammal, it becomes very important indeed.
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We see this with avian flu (as the authors note). Many variants that infect ducks and other waterfowl are low path in other birds, such as chickens, in part because they lack a polybasic FCS at the cleavage site (a spot between the two main parts...
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...of the hemagglutinin (HA) protein, flu's version of the Spike protein).

HA and Spike are the parts of each virus that stick to the surface of our cells and facilitate entry into cells.

But something interesting happens in the crowded conditions of chicken farms...
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...from time to time. A variant of low path evolves into high path avian flu by acquiring a polybasic FCS. This puts the HA on a hair trigger in terms of being cleaved into separate chunks thus making it able to facilitate entry to the cells of chickens' respiratory tracts.
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This can involve just a single mutation, which might be present at low frequency in ducks, or might evolve from a de novo mutation in chickens once there is strong selection in a chicken farm for a functional FCS.
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So, three products of chicken farms: eggs, meat and furin cleavage sites...the latter of which make the virus lethal for both chickens and, should they be exposed, humans.
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Back to CoVs. In samples from two European bats, the authors found SARSr-CoVs that were just one mutation away from a functional FCS. But minor variants were sequenced from each that *had* a functional FCS already, just as is seen with some low path flu.
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Now, as they note, this could just be sequencing error. But let's imagine for a minute that it is not. Drop that virus into, say, a raccoon dog farm, and it will quickly be selected to generate an efficient respiratory pathogen. Big H/T to @stgoldst here.
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By the way, when I say drop, I mean it literally.

Now, instead, imagine the low frequency variant is not present in the progenitor SC2 population in bat poop that lands in a raccoon dog cage. Just as on a chicken farm with flu, a single de novo mutation within...
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...the unlucky raccoon dog that is infected with the bat virus - or in another raccoon dog down a small transmission chain on the farm - provides a tremendous advantage to the lucky virus, and its progeny then sweep through the farm.
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We see it repeatedly with avian flu. These results show that SARS-CoV-2 is likely just one more instance of this process, just in a different virus. Bat viruses related to SC2 are just one small, predictable step away - or no steps at all in rare cases - from an FCS.
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Hence, the authors' conclusion:
"Furin cleavage thus likely emerged from the SrC bat reservoir via molecular mechanisms conserved across reservoir-bound RNA viruses, supporting a natural origin of SARS-CoV-2."
Doesn't get more important than that. Tour de force.
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Coda: Rural Hubei province, particularly out west in Enshi Prefecture, had a *massive* industry of farming mammals such as raccoon dogs for fur and food. Perhaps 3/4 million animals culled in early 2020, with none to my knowledge tested for SC2 by PCR or serology.
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It is also home to one of the biggest cave complexes in China, with large populations of the horseshoe bats that harbor SC2-related bat CoVs.

See this report from the intrepid @mstandaert.
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washingtonpost.com/world/asia_pac…

"Hundreds of caves are spread throughout the mountains of Enshi prefecture, an agricultural corner of China's Hubei province. The most majestic, Tenglong...is one of China's largest karst cave systems, spanning 37 miles of passages that contain numerous bats.
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"Nearby are small farms that collectively housed hundreds of thousands of wild mammals such as civets, ferret badgers and raccoon dogs before the pandemic, farm licenses show."
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Here's one civet farm visited by @mstandaert, just downhill from one of those caves.
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