Laboratory of Functional Viromics (LETKO)
@fviromics.bsky.social
Dr. Michael Letko’s Laboratory of Functional Viromics | we study zoonotic potential of novel viruses.
For more information, check out our website: https://labs.wsu.edu/lofv/
For more information, check out our website: https://labs.wsu.edu/lofv/
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Aminopeptidase N is a receptor for hedgehog merbecoviruses
Merbecoviruses, closely related to the highly pathogenetic Middle East Respiratory Syndrome Coronavirus (MERS-CoV), circulate in hedgehogs throughout Europe and Asia, raising concerns about zoonotic t...
tinyurl.com
New preprint! If some merbecoviruses use DPP4 and others use ACE2, what do those hedgehog merbecoviruses use?! As it turns out, neither! In our latest study, we uncover the "missing" receptor for the MERS-related viruses in hedgehogs. [These findings were first shared at ASV this year] (1/6)
Reposted by Laboratory of Functional Viromics (LETKO)
Big thanks to Vic Jefferson, Nick Catanzaro, Ralph Baric and Michael Letko @fviromics.bsky.social and big congrats to
@jarelelgin.bsky.social
, our talented PhD student who led the work!! 🥳🥳
@jarelelgin.bsky.social
, our talented PhD student who led the work!! 🥳🥳
October 28, 2025 at 5:07 AM
Big thanks to Vic Jefferson, Nick Catanzaro, Ralph Baric and Michael Letko @fviromics.bsky.social and big congrats to
@jarelelgin.bsky.social
, our talented PhD student who led the work!! 🥳🥳
@jarelelgin.bsky.social
, our talented PhD student who led the work!! 🥳🥳
Reposted by Laboratory of Functional Viromics (LETKO)
The bat viruses with the closest spike or loop2 to that of nvHKU5r-CoV were also sampled in provinces with primary mink fur processing and wholesale hubs, further implicating fur farming as an important risk factor for virus spillover.
October 28, 2025 at 5:07 AM
The bat viruses with the closest spike or loop2 to that of nvHKU5r-CoV were also sampled in provinces with primary mink fur processing and wholesale hubs, further implicating fur farming as an important risk factor for virus spillover.
Reposted by Laboratory of Functional Viromics (LETKO)
Lastly we did comprehensive recombination and molecular dating analysis to explore the origins of this nvHKU5r-CoV. Our findings support that the virus transmitted from bats to mink within the last decade, consistent with an expansion of mink fur farming in China.
October 28, 2025 at 5:07 AM
Lastly we did comprehensive recombination and molecular dating analysis to explore the origins of this nvHKU5r-CoV. Our findings support that the virus transmitted from bats to mink within the last decade, consistent with an expansion of mink fur farming in China.
Reposted by Laboratory of Functional Viromics (LETKO)
AlphaFold3 co-structure predictions were also consistent with entry when this single mutation was introduced, revealing the likely molecular interaction that enables hACE2 compatibility.
October 28, 2025 at 5:07 AM
AlphaFold3 co-structure predictions were also consistent with entry when this single mutation was introduced, revealing the likely molecular interaction that enables hACE2 compatibility.
Reposted by Laboratory of Functional Viromics (LETKO)
Using a safe, replication competent VSV system expressing the nvHKU5r-CoV spike we did passaging in mixed cells expressing both Pabr and hACE2. To our surprise, the spikes acquired a single mutation on the loop2, R548S, which enabled hACE2 usage!
October 28, 2025 at 5:07 AM
Using a safe, replication competent VSV system expressing the nvHKU5r-CoV spike we did passaging in mixed cells expressing both Pabr and hACE2. To our surprise, the spikes acquired a single mutation on the loop2, R548S, which enabled hACE2 usage!
Reposted by Laboratory of Functional Viromics (LETKO)
Then we asked, since ACE2 ortholog usage seems to shift quite easily in these viruses, could nvHKU5r-CoV potentially use human ACE2?
October 28, 2025 at 5:07 AM
Then we asked, since ACE2 ortholog usage seems to shift quite easily in these viruses, could nvHKU5r-CoV potentially use human ACE2?
Reposted by Laboratory of Functional Viromics (LETKO)
We further confirmed our pseudovirus results with luciferase reporter live virus, showing that nvHKU5r-CoV specifically replicated well in both PabrACE2 and nvACE2 expressing cells.
October 28, 2025 at 5:07 AM
We further confirmed our pseudovirus results with luciferase reporter live virus, showing that nvHKU5r-CoV specifically replicated well in both PabrACE2 and nvACE2 expressing cells.
Reposted by Laboratory of Functional Viromics (LETKO)
Impressively, AlphaFold3 predictions of RBD-ACE2 pairs were very consistent with pseudovirus results! RBDs with ACE2 entry had consistent binding footprints while RBDs without entry were predicted to bind inaccessible parts of the ACE2s.
October 28, 2025 at 5:07 AM
Impressively, AlphaFold3 predictions of RBD-ACE2 pairs were very consistent with pseudovirus results! RBDs with ACE2 entry had consistent binding footprints while RBDs without entry were predicted to bind inaccessible parts of the ACE2s.
Reposted by Laboratory of Functional Viromics (LETKO)
...the only two long loop2 RBDs that can use nvACE2 being nvHKU5r-CoV and Q265, but not WZ2! This shows that loop2 is a key determinant for enabling the use of non-bat ACE2s.
October 28, 2025 at 5:07 AM
...the only two long loop2 RBDs that can use nvACE2 being nvHKU5r-CoV and Q265, but not WZ2! This shows that loop2 is a key determinant for enabling the use of non-bat ACE2s.
Reposted by Laboratory of Functional Viromics (LETKO)
Taking these RBDs in the lab, we show with pseudovirus assays that all HKU5r-CoVs can use their native P abramus ACE2, but only few can use mink ACE2, especially ones with long loop2s...
October 28, 2025 at 5:07 AM
Taking these RBDs in the lab, we show with pseudovirus assays that all HKU5r-CoVs can use their native P abramus ACE2, but only few can use mink ACE2, especially ones with long loop2s...
Reposted by Laboratory of Functional Viromics (LETKO)
This part of the RBD corresponds to a loop in the RBD structure called loop2, known to have different lengths between HKU5r-CoVs. By examining the evolution of the loop2 we show a single deletion to a shorter genotype which has in turn recombined into many different RBDs.
October 28, 2025 at 5:07 AM
This part of the RBD corresponds to a loop in the RBD structure called loop2, known to have different lengths between HKU5r-CoVs. By examining the evolution of the loop2 we show a single deletion to a shorter genotype which has in turn recombined into many different RBDs.
Reposted by Laboratory of Functional Viromics (LETKO)
However, just like all CoVs merbecoviruses are notorious for recombining parts of their genome, especially the spike. Looking more closely, we detected one small part of the RBD where nvHKU5r-CoVs were curiously closer to another bat virus, Q265!
October 28, 2025 at 5:07 AM
However, just like all CoVs merbecoviruses are notorious for recombining parts of their genome, especially the spike. Looking more closely, we detected one small part of the RBD where nvHKU5r-CoVs were curiously closer to another bat virus, Q265!
Reposted by Laboratory of Functional Viromics (LETKO)
The mink HKU5 virus (nvHKU5r-CoV) was sampled in Shendong and seems to be overall closest to different bat HKU5s sampled in P. abramus bats across south and east China. 🦇
When focusing on the spike and RBD, one virus, WZ2, sampled in Zhejiang, is the single closest relative.
When focusing on the spike and RBD, one virus, WZ2, sampled in Zhejiang, is the single closest relative.
October 28, 2025 at 5:07 AM
The mink HKU5 virus (nvHKU5r-CoV) was sampled in Shendong and seems to be overall closest to different bat HKU5s sampled in P. abramus bats across south and east China. 🦇
When focusing on the spike and RBD, one virus, WZ2, sampled in Zhejiang, is the single closest relative.
When focusing on the spike and RBD, one virus, WZ2, sampled in Zhejiang, is the single closest relative.
Reposted by Laboratory of Functional Viromics (LETKO)
New preprint alert!! 🚨🚨🚨in collaboration with the Letko @fviromics.bsky.social and Baric labs!
Just in case you're tired of sarbecoviruses, this time we looked at ACE2-using merbecoviruses! specifically the first HKU5r-CoVs detected in mink a couple of years ago.
www.biorxiv.org/content/10.1...
Just in case you're tired of sarbecoviruses, this time we looked at ACE2-using merbecoviruses! specifically the first HKU5r-CoVs detected in mink a couple of years ago.
www.biorxiv.org/content/10.1...
Structural and phenotypic plasticity of the RBD loop2 region is a key determinant for HKU5r-CoVs’ emergence in mink
The emergence of novel coronaviruses from animal reservoirs continues to pose a significant zoonotic threat. Here, we investigate the evolutionary origins and virological properties of a recently repo...
www.biorxiv.org
October 28, 2025 at 5:07 AM
New preprint alert!! 🚨🚨🚨in collaboration with the Letko @fviromics.bsky.social and Baric labs!
Just in case you're tired of sarbecoviruses, this time we looked at ACE2-using merbecoviruses! specifically the first HKU5r-CoVs detected in mink a couple of years ago.
www.biorxiv.org/content/10.1...
Just in case you're tired of sarbecoviruses, this time we looked at ACE2-using merbecoviruses! specifically the first HKU5r-CoVs detected in mink a couple of years ago.
www.biorxiv.org/content/10.1...
New pre-print! Where did the HKU5 viruses recently reported in mink come from and where might they go next? In this collaboration with the Sato lab, we explore the recombinant origins of mink HKU5 viruses and test what it would take for human ACE2 use. Intermediate hosts are important for zoonosis!
Structural and phenotypic plasticity of the RBD loop2 region is a key determinant for HKU5r-CoVs' emergence in mink
The emergence of novel coronaviruses from animal reservoirs continues to pose a significant zoonotic threat. Here, we investigate the evolutionary origins and virological properties of a recently repo...
shorturl.at
October 27, 2025 at 1:07 AM
New pre-print! Where did the HKU5 viruses recently reported in mink come from and where might they go next? In this collaboration with the Sato lab, we explore the recombinant origins of mink HKU5 viruses and test what it would take for human ACE2 use. Intermediate hosts are important for zoonosis!
Reposted by Laboratory of Functional Viromics (LETKO)
I love the kind of papers that I sometimes get from the cryo-EM bot. Hedgehog coronavirus!🦔
Aminopeptidase N is a receptor for hedgehog merbecoviruses pubmed.ncbi.nlm.nih.gov/40950050/ #cryoem
September 16, 2025 at 7:01 PM
I love the kind of papers that I sometimes get from the cryo-EM bot. Hedgehog coronavirus!🦔
Reposted by Laboratory of Functional Viromics (LETKO)
Reposted by Laboratory of Functional Viromics (LETKO)
Excited to share our study reporting the first Sin Nombre virus (SNV) genome sequences from the Northwestern U.S., and the first ever from a vole host.
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...
First Sin Nombre virus (Orthohantavirus sinnombreense) genome sequences from the Northwestern United States
We report the first Sin Nombre virus (SNV) genome sequences from the Northwestern United States and the first SNV sequences recovered from voles. Analysis of samples collected from 189 individual rode...
www.biorxiv.org
September 17, 2025 at 3:48 PM
Excited to share our study reporting the first Sin Nombre virus (SNV) genome sequences from the Northwestern U.S., and the first ever from a vole host.
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...
If you haven’t already, you should check out our latest study identifying the host receptor used by merbecoviruses that circulate European and Asian hedgehogs. It’s a surprising finding that unlocks the entire group of viruses for researchers to study further!
Aminopeptidase N is a receptor for hedgehog merbecoviruses
Merbecoviruses, closely related to the highly pathogenetic Middle East Respiratory Syndrome Coronavirus (MERS-CoV), circulate in hedgehogs throughout Europe and Asia, raising concerns about zoonotic t...
www.biorxiv.org
September 14, 2025 at 3:41 PM
If you haven’t already, you should check out our latest study identifying the host receptor used by merbecoviruses that circulate European and Asian hedgehogs. It’s a surprising finding that unlocks the entire group of viruses for researchers to study further!
Reposted by Laboratory of Functional Viromics (LETKO)
This was a large team effort. Big thank you to our structural collaborator, James Rini at University of Toronto, Craig Wilen at Yale, the Baric lab at UNC, our Italian collaborators for discovering these viruses and sharing cool sequence data, and of course, Vic, the talented postdoc in my lab.(6/6)
September 4, 2025 at 4:48 AM
This was a large team effort. Big thank you to our structural collaborator, James Rini at University of Toronto, Craig Wilen at Yale, the Baric lab at UNC, our Italian collaborators for discovering these viruses and sharing cool sequence data, and of course, Vic, the talented postdoc in my lab.(6/6)
Reposted by Laboratory of Functional Viromics (LETKO)
Reposted by Laboratory of Functional Viromics (LETKO)
To expand on the RBD clade classifications from our last paper:
CLADE 1 = MERS-CoV, HKU4 = DPP4 users
CLADE 2 = HKU5 complex, HKU25, H.Savii = ACE2 users
CLADE 3 = PDF2180, NeoCoV = ACE2 users
CLADE 4 = ErinCoVs (all of them) = APN users
Such receptor diversity for one subgenus! 🤩
(5/6)
CLADE 1 = MERS-CoV, HKU4 = DPP4 users
CLADE 2 = HKU5 complex, HKU25, H.Savii = ACE2 users
CLADE 3 = PDF2180, NeoCoV = ACE2 users
CLADE 4 = ErinCoVs (all of them) = APN users
Such receptor diversity for one subgenus! 🤩
(5/6)
September 4, 2025 at 4:48 AM
To expand on the RBD clade classifications from our last paper:
CLADE 1 = MERS-CoV, HKU4 = DPP4 users
CLADE 2 = HKU5 complex, HKU25, H.Savii = ACE2 users
CLADE 3 = PDF2180, NeoCoV = ACE2 users
CLADE 4 = ErinCoVs (all of them) = APN users
Such receptor diversity for one subgenus! 🤩
(5/6)
CLADE 1 = MERS-CoV, HKU4 = DPP4 users
CLADE 2 = HKU5 complex, HKU25, H.Savii = ACE2 users
CLADE 3 = PDF2180, NeoCoV = ACE2 users
CLADE 4 = ErinCoVs (all of them) = APN users
Such receptor diversity for one subgenus! 🤩
(5/6)
Reposted by Laboratory of Functional Viromics (LETKO)
We also provide not one, but TWO cryo-EM co-structures of ErinCoV RBDs bound to hedgehog APN. Both German and Italian hedgehog coronaviruses interact with hedgehog APN identically. Binding assays show that ErinCoVs have a lower affinity for APN than other CoVs have for their receptors. (4/6)
September 4, 2025 at 4:48 AM
We also provide not one, but TWO cryo-EM co-structures of ErinCoV RBDs bound to hedgehog APN. Both German and Italian hedgehog coronaviruses interact with hedgehog APN identically. Binding assays show that ErinCoVs have a lower affinity for APN than other CoVs have for their receptors. (4/6)
Reposted by Laboratory of Functional Viromics (LETKO)
Aminopeptidase N- the classic alpha-CoV receptor - facilitates ErinCoV entry. And we don't show this for just one virus, we show it for all of them. Every merbecovirus in hedgehogs across Europe and Asia- from ErinCoV-12-19 to HKU31 - all use APN. This is a first for beta-CoVs! (2/6)
September 4, 2025 at 4:48 AM
Aminopeptidase N- the classic alpha-CoV receptor - facilitates ErinCoV entry. And we don't show this for just one virus, we show it for all of them. Every merbecovirus in hedgehogs across Europe and Asia- from ErinCoV-12-19 to HKU31 - all use APN. This is a first for beta-CoVs! (2/6)