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Slack / Private Message Drop, p.340 [SLACK_000554] · slack_pm:msg:03584

Date: 2020-12-23 03:58
Type: chat message · slack
recipient: Kristian G. Andersen, Edward C. Holmes, Andrew Rambaut
speaker: Robert F. Garry

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Two interspecies transfers of SC2 have occurred. Human to mouse in the lab. Human to mink and back on the fur farms. Residues Q493 and N501 are also involved. N501Y enables replication of SC2 in mice; Q493H makes the mouse adapted SC2 pathogenic prob by increasing replication. A SC2 Q493K change can increase both replication and pathogenesis in mice.

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2020-12-23 03:46 Robert F. Garry open

Cliff Notes version:
2020-12-23 03:51 Robert F. Garry open

Two RBD residues (residues 479 and 487) had to mutate to enable civet SC1 (the 99+% virus) to jump to humans. These changes allow interaction with contact residues on human ACE2. JVI paper sums it nicely. This happened more than once with SC1.
2020-12-23 03:53 Robert F. Garry open

The two SC1 residues are equivalent in how they interact with ACE2 to to SC2 RBD residues Q493 and N501.
2020-12-23 03:58 Robert F. Garry

Two interspecies transfers of SC2 have occurred. Human to mouse in the lab. Human to mink and back on the fur farms. Residues Q493 and N501 are also involved. N501Y enables replication of SC2 in mice; Q493H makes the mouse adapted SC2 pathogenic prob by increasing replication. A SC2 Q493K change can increase both replication and pathogenesis in mice.
2020-12-23 04:04 Robert F. Garry open

Several different changes in SC2 to enable replication in mink. All involve changing the contact residues in RBD toenable better interaction with mink ACE2. One of the changes is N501T. I don't think mink NEED to change Q493because their contact residues K33/Y34 are similar to human K33/H34.
2020-12-23 04:08 Robert F. Garry open

Kristian asked why the change in SC1 was so fast - I think the answer is that civets are probably already sampling the mutational space of SC1 RBD residues 479 and 487 because these are important epitopes. If there are the right quasispecies with immune escape mutants in the civet that you picked for dinner these would be selected on your human ACE2.
2020-12-23 04:14 Robert F. Garry open

This brings us to Nelly and her cousins. Humans with long term infections are also generating SC2 immune escape mutants. N501Y is likely one of those. It also has the selective advantage that it increases binding to ACE2. I think this is a strong aromatic:aromatic interaction between Spike 501Y and ACE2 41Y, but yeah would like to see that ina cryo structure from Andrew Ward.
2020-12-23 04:15 Robert F. Garry open

In Andrew's virological post you see the selection of 501Y - it goes from partial (a quasi-species) to a fixed variant.

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