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The Veesler Lab Profile picture
@veeslerlab
Oct 26, 2021 • 12 tweets • 6 min read • Read on X
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Have you heard of the recently discovered 8th human-infecting #coronavirus designated CCoV-HuPn-2018?
We reveal the architecture of its spike (ie infection machinery), receptor usage and antigenic properties!

Led by @aletortorici

1/12

biorxiv.org/content/10.110…
CCoV-HuPn-2018 is a canine-feline recombinant alpha-#coronavirus isolated from the respiratory swab of a child hospitalized with pneumonia, indicating that more coronaviruses are spilling over to humans than previously appreciated.

2/12

academic.oup.com/cid/advance-ar…
We determined #cryoEM structures of the CCoV-HuPn-2018 spike in two markedly different conformational states which we propose to correspond to two snapshots of viral entry.

3/12
The CCoV-HuPn-2018 spike harbors a domain 0 upstream from the 'canonical NTD' (aka domain A) and they share the same fold (despite <13% aa sequence identity). Domain 0 interacts with host carbohydrates for some alphacoronaviruses and perhaps CCoV-HuPn-2018 does too.

4/12
Based on structural similarity with PRCV/TGEV, we postulated that the CCoV-HuPn-2018 spike receptor-binding domain (RBD, domain B) could bind APN which is an entry receptor for some alphacoronaviruses, including PRCV/TGEV.

5/12
The CCoV-HuPn-2018 spike receptor-binding domain (RBD, domain B) binds to feline, canine & porcine APN orthologs but not human APN (similar to PRCV/TGEV), which is surprising as CCoV-HuPn-2018 was isolated from an hospitalized child.

6/12
It turns out that one of the differences between human APN and feline, canine & porcine APNs is a Thr to Arg residue substitution at position 741, in the receptor region recognized by PRCV/TGEV.

7/12
Previous work showed that abrogation of this glycosylation site prevented binding of the TGEV RBD to cell-surface expressed porcine APN and we wondered if it could be the case for CCoV-HuPn-2018 as well.

8/12

journals.plos.org/plospathogens/…
Feline, canine & porcine APNs, and human R741T APN (N739 oligosaccharide knockin mutant) render cells permissive to CCoV-HuPn-2018 spike-mediated entry and soluble APNs inhibit this in a concentration-dependent manner. Thus APN is an entry receptor for CCoV-HuPn-2018!

9/12
APN single nucleotide polymorphisms have been described in humans, including at R741 (wo introducing a glycan) and we think that such variations might be present in infected individuals.
Please get in touch if interested in helping us find out.

10/12

sciencedirect.com/science/articl…
Polyclonal plasma neutralizing antibodies elicited by 'common cold' 229E infection also cross-neutralized (to various extent) CCoV-HuPn-2018 spike-mediated entry, which has the potential to reduce disease severity of this virus in humans.

11/12
This work would not have been possible without @coronalexington Anshu Joshi @YoungjunPark11 and our fantastic collaborators @atelentia @LanzavecchiaB @DavideCorti6 @jbloom_lab and many others not on twitter

12/12

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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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