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The Veesler Lab Profile picture
@veeslerlab
Oct 14, 2021 • 7 tweets • 5 min read • Read on X
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We identified a broadly neutralizing sarbecovirus antibody (S2K146) in collaboration with Matteo Samuele Pizzuto & @DavideCorti6
Work led by @YoungjunPark11 Anna De Marco @tylernstarr @JZhuoming

1/7
biorxiv.org/content/10.110…
S2K146 binds and broadly neutralizes several SARS-CoV-1-like and SARS-CoV-2-like viruses (clades 1a/1b). It inhibits BtKY72 (clade 3) K493Y/T498W S pseudovirus, as we previously showed that these 2 mutations enable this bat virus to use hACE2.

biorxiv.org/content/10.110…

2/7 Image
Our #cryoEM structure reveals that S2K146 'mimics' ACE2, as 75% of the residues participating in the epitope are also part of the ACE2 binding site, and is therefore not affected by known variants.

3/7 Image
Although the receptor-binding motif is highly divergent among sarbecoviruses, neutralization of SARS-CoV-1 is explained by the conservation of many epitope residues with SARS-CoV-2, consistent with the ability of each of these RBDs to bind hACE2.

4/7 Image
S2K146-mediated neutralization of SARS-CoV-2 is exceedingly difficult to escape, due to severe dampening of ACE2 binding, and the single escape mutant isolated (Y489H) had markedly reduced fitness.

5/7 Image
S2K146 inhibits ACE2 attachment competitively, triggers S1 shedding and premature spike refolding to the postfusion state and protects hamsters against #SARSCoV2 beta (B.1.351) challenge in a stringent therapeutic (post-exposure) setting.

6/7 Image
Thank you so much to @coronalexington @SamK_Zepeda @johnbowenbio Kaiti Sprouse Anshu Joshi and our wonderful collaborators including @jbloom_lab @vsv512 @neyts_johan @FLempp and many others not on twitter!

7/7

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More from @veeslerlab

The Veesler Lab Profile picture
Nov 1, 2024
Excited to share our latest work elucidating the mechanisms of coronavirus entry into cells!

Led by @Dr_MattMcCallum on our side in collaboration with Huan Yan's lab (TaiKang Center for Life and Medical Sciences)



1/5nature.com/articles/s4158…
In 2019, we proposed w @coronalexington @axiong_x that coronavirus entry into cells involves a spike (S) molecular ratcheting mechanism & discovered that antibodies could functionally mimic the receptor by inducing these S conformational changes

2/5
cell.com/cell/fulltext/…
This movie made with @janetiwasa summarizes this ratcheting mechanism

3/5
Read 6 tweets
The Veesler Lab Profile picture
Jul 9, 2024
How many times did coronaviruses evolve the ability to use ACE2 as receptor for infection? Find out by reading this @biorxivpreprint in collab with Huan Yan (Wuhan Univ)

Led by Ma CB, Liu C @YoungjunPark11 Tang J & Chen J

@HHMINEWS
@UWBiochemistry

1/9
 biorxiv.org/content/10.110…
We previously described the unexpected discovery that MERS-related coronaviruses (MERSr-CoVs) discovered in African bats use ACE2 as receptor instead of the MERS-CoV receptor DPP4 (as described in this thread )



2/9
nature.com/articles/s4158…
It turns out that recently described MERSr-CoVs identified in European bats (MOW15-22 & PnNL2018B) with highly divergent receptor-binding motif (RBM) also use ACE2 but with a distinct and much narrower species tropism

3/9 Image
Read 9 tweets
The Veesler Lab Profile picture
Mar 14, 2024
A few months ago, we asked if imprinting impacts immune responses to the recently updated XBB.1.5 spike (S) #COVID19 booster? The peer-reviewed version of our manuscript is now available
@HHMINEWS @UWBiochemistry

1/11

cell.com/immunity/fullt…
The original thread describing our results is below


2/11
During the review process, we added data showing elicitation of broadly neutralizing polyclonal plasma antibodies (Abs) against a wider ranger of #SARSCoV2 variants (now including HK.3 and JN.1) and at a later time point (~50 days post XBB.1.5 booster vaccination)

3/11 Image
Read 11 tweets
The Veesler Lab Profile picture
Jan 10, 2024
Are you wondering how the human coronavirus HKU1 recognizes the TMPRSS2 host receptor?

Find out in our @biorxivpreprint led by
@Dr_MattMcCallum @YoungjunPark11

@HHMINEWS @UWBiochemistry

1/26
biorxiv.org/content/10.110…
HKU1 was discovered in 2005 from a patient with pneumonia (it was circulating for ≥10 years) and is endemic in humans. HKU1 is an embecovirus, a subgenus for which the entry process into cells is less well understood than for most other betaCoVs such as #SARSCoV2

2/26
Recently, @Virus_Immunity @JBuchrieser @virusfusion007 and colleagues showed that human TMPRSS2 is an entry receptor for HKU1

3/26

nature.com/articles/s4158…
Read 26 tweets
The Veesler Lab Profile picture
Dec 14, 2023
Can we design #COVID19 vaccines that are largely insensitive to viral evolution? Find out by reading our @biorxivpreprint preprint

Led by @0327jimin

@HHMINEWS @UWBiochemistry

1/22

biorxiv.org/content/10.110…
Coronavirus spike (S) glycoproteins comprise the S1 subunit, which mediates attachment to host receptor(s), and the S2 subunit (fusion machinery) that promotes fusion of the viral and host membranes to initiate infection

2/22 Image
The S2 subunit (fusion machinery) is much more conserved than the S1 subunit (comprising the RBD and NTD), and harbors several antigenic sites targeted by broadly neutralizing and protective monoclonal antibodies (Abs)

3/22
Read 22 tweets
The Veesler Lab Profile picture
Dec 1, 2023
Is imprinting impacting immune responses to the recently updated XBB.1.5 spike (S) #COVID19 booster? Find out by reading our preprint or this thread!

Led by @aletortorici

@HHMINEWS @UWBiochemistry

1/18

biorxiv.org/content/10.110…
Immune imprinting - AKA original antigenic sin - describes how the first exposure to a virus shapes the immunological outcome of subsequent exposures to antigenically related strains.

2/18
Last year, we showed that Omicron infection of Wuhan-Hu-1 (Wu) mRNA vaccinees recalls cross-reactive memory B cells specific for epitopes shared by multiple #SARSCoV2 variants rather than priming naive B cells binding Omicron RBD-specific epitopes

3/18
science.org/doi/10.1126/sc…
Image
Read 18 tweets

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