Evolutionary potential of the SARS-CoV-2 receptor binding domain (RBD)

 

Jesse Bloom

Fred Hutch Cancer Research Center / UW Genome Sciences / HHMI

 

Slides at https://slides.com/jbloom/gs-retreat-2020​

 

@jbloom_lab

SARS-CoV-2 virions are decorated by spike proteins that mediate viral entry

virion image from https://phil.cdc.gov/Details.aspx?pid=23312

A key portion of the spike is the receptor-binding domain (RBD)

The RBD binds ACE2 receptor on cells

Neutralizing antibodies often bind RBD & block interaction with ACE2

Yeast display to measure how mutations affect RBD folding and ACE2 binding

RBD

fluorescent ACE2

yeast

fluorescent tag on RBD

Starr*, Greaney*, ..., Bloom. Cell (2020)

Library of yeast, each expressing different RBD mutant with identifying 16 nt barcode

Starr*, Greaney*, ..., Bloom. Cell (2020)

Maps of how mutations affect RBD folding and ACE2 binding

Starr*, Greaney*, ..., Bloom. Cell (2020)

• Interactive maps
• Maps projected on RBD structure

We then mapped how mutations affect binding of anti-viral antibodies to RBD

Greaney*, Starr*, Gilchuk*, Zost*, ..., Crowe, Bloom. bioRxiv (2020)

Greaney*, Starr*, Gilchuk*, Zost*, ..., Crowe, Bloom. bioRxiv (2020)

Escape map from one antibody

(click here for interactive visualization)

Greaney*, Starr*, Gilchuk*, Zost*, ..., Crowe, Bloom. bioRxiv (2020)

Escape maps for three antibodies

Subtle differences between COV2-2165 & COV2-2832 (e.g., sites 486, 487) validate in neutralization assays (see here).

Greaney*, Starr*, Gilchuk*, Zost*, ..., Crowe, Bloom. bioRxiv (2020)

We can organize antibodies in space of escape mutations

Summary

• We can create phenotypic maps of how all mutations to SARS-CoV-2 RBD affect folding, function, and antigenicity

Summary

• We can create phenotypic maps of how all mutations to SARS-CoV-2 RBD affect folding, function, and antigenicity

• These maps tell us how virus can escape from antibodies.

Summary

• We can create phenotypic maps of how all mutations to SARS-CoV-2 RBD affect folding, function, and antigenicity

• These maps tell us how virus can escape from antibodies.

• The maps are useful for understanding how ongoing viral evolution affects therapeutic antibodies and immunity

Summary

Bloom lab (Fred Hutch)

• Kate Crawford
• Adam Dingens
• Andrea Loes
• Rachel Eguia

 

Crowe lab (Vanderbilt)

• Elad Binshtein

 

Whelan lab (Wash U)

• Sean Whelan
• Paul Rothlauf
• Zhuoming Liu

 

King lab (Univ Wash)

• Neil King
• Dan Ellis

 

Veesler lab (Univ Wash)

• David Veesler
• Alexandra Walls

These slides:

https://slides.com/jbloom/gs-retreat-2020

Interested in this work? Please see the following papers for more details:

• Greaney*, Starr*, Gilchuk*, Zost*, ..., Crowe, Bloom. bioRxiv (2020)

• Starr*, Greaney*, ..., Bloom. Cell (2020)