Thread by @veeslerlab

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