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!! 🥳🥳

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.

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.

AlphaFold3 co-structure predictions were also consistent with entry when this single mutation was introduced, revealing the likely molecular interaction that enables hACE2 compatibility.

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!

Then we asked, since ACE2 ortholog usage seems to shift quite easily in these viruses, could nvHKU5r-CoV potentially use human ACE2?

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.

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.

...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.

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...

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.

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!

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.

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...

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!

I love the kind of papers that I sometimes get from the cryo-EM bot. Hedgehog coronavirus!🦔

www.nature.com/articles/s41... Stunning work from the Chandran lab!

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...

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!

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)

🧐 if you know, then you know www.biorxiv.org/content/10.1...

🧐 if you know, then you know www.biorxiv.org/content/10.1...

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)

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)

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)

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)

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)

Breakthroughs happen when diverse expertise is woven together. Collaboration can be messy—different vocabularies, different tools—but it’s worth it. We made a video with @MinuteEarth about it. 🎥 @fviromics.bsky.social @payeldas.bsky.social & Drew Kramer #EEID

Always great to see Simon Lab Alumni go on to achieve great things! Dr. Michael Letko gave an excellent keynote at #ASV2025 on "Uncovering novel receptor use in beta-coronaviruses with functional viromics" check out his lab's work here: labs.wsu.edu/lofv/ @amersocvirology.bsky.social

🚨 Our team just released a reproducible Docker pipeline for RNAseq assembly and annotation designed for nonmodel organisms! We're using it to explore how bats manage viral infections, but it's built for broad utility in wildlife transcriptomics. @viralemergence.org www.biorxiv.org/content/10.1...

LoFV will be all over ASV in Montreal this year! I am giving a plenary talk Monday evening and will share an all new study that hasn’t been pre-printed. Also, look out for our talented post-doc, Victoria Jefferson, on Wednesday (P26-15) and skilled collaborator, Nick Catanzaro, on Tuesday (W13-6).

Exciting news! A few weeks ago, the TWiV podcast reviewed a paper from Michael Letko's lab (@fviromics.bsky.social) featuring one of our graduate students as a co-first author. Give it a listen! www.microbe.tv/twiv/twiv-12...

🚨Our new study out today in Nature Communications. Bats can asymptomatically host multiple viruses while remaining apparently healthy. Here we identify how interferon-mediated responses protect bats and identify molecular adaptations in GBP1. #LZCI Link: www.nature.com/articles/s41...

Our study assessing global merbecovirus entry and showing the receptor for HKU5 viruses was featured by the editors on the Nature Communications highlights page. Give it a read if you haven’t already! www.nature.com/collections/...

Here’s a great write up of our latest work with HKU5 coronaviruses from the WSU press office! news.wsu.edu/press-releas...

Our study screening merbecoviruses for receptor tropism and identifying the receptor for HKU5 coronaviruses was highlighted in This Week in Virology with Vincent Racaniello!What great discussion of the study! www.microbe.tv/twiv/twiv-12...

very nice work from the @fviromics.bsky.social and Baric labs uncovering some of the ways these merbecoviruses can use ACE2 as their entry receptor! www.nature.com/articles/s41...

New paper about ACE2 using Merbecovirus. Hot stuff. So hot but you can't Letko. @fviromics.bsky.social and Nick Catanzaro. www.nature.com/articles/s41... #ACE2 #emergingviruses #bats #batman #MERS #HKU5

In our latest study we used alphafold 3 to predict the interaction between HKU5 virus spike protein and its receptor, ACE2. Using a 2021-based dataset, AF3 produced a new interface that has now been validated by other groups with cryoEM. What other new interactions can AF3 show us? rdcu.be/en7Dy

Our study screening the majority of all published Merbecovirus RBD’s for cell entry phenotypes is now published in Nature Communications! (1/5) shorturl.at/gYz4E

Bat cells for virology and innate immunology. Sneha Khedkar highlights our study in The Scientist: www.the-scientist.com/bat-cells-in... Link to original paper: journals.plos.org/plosbiology/... @fviromics.bsky.social @stephseifertphd.bsky.social

Choose Science. Choose Europe. A new Marie Skłodowska-Curie Actions Postdoctoral Fellowships 2025 call is now open. With a budget of €404.3 million, it will support around 1,650 researchers from Europe and beyond. Apply by 10 September → europa.eu/!fBTMgF

Research on the #bat innate #ImmuneResponse to pathogens is hindered by a lack of lab reagents. @fviromics.bsky.social @stephseifertphd.bsky.social @virology.bsky.social &co generate new bat #CellLines, enabling studies on viral susceptibility & immune responses @plosbiology.org 🧪 plos.io/4jkXukf

Research on the #bat innate #ImmuneResponse to pathogens is hindered by a lack of lab reagents. @fviromics.bsky.social @stephseifertphd.bsky.social @virology.bsky.social &co generate new bat #CellLines, enabling studies on viral susceptibility & immune responses @plosbiology.org 🧪 plos.io/4jkXukf

On the cover of the Journal of Virology this month with all our bat colleagues! #Bats #LZCI @stephseifertphd.bsky.social Associated article: journals.asm.org/doi/10.1128/...

🚨Latest BAT publication now out in @plosbiology.org with @fviromics.bsky.social @stephseifertphd.bsky.social and others. #PLOSBiology 🦇 Proud of our PhD candidate, Victoria Gonzalez! #LZCI journals.plos.org/plosbiology/... More detailed post from my colleague, Dr. Letko: bsky.app/profile/fvir...

Our study developing new bat cell lines is now published with PLoS Biology! We made new bat cell lines for virology research that are immunocompetent and support entry and replication of orthohantaviruses and several others. tinyurl.com/ymfduzjw

Are bats tolerant of all viruses? With a comparative -omics approach, we show that Egyptian fruit bat cells show both antiviral and pro-inflammatory immune responses to infection with Zika virus while our Jamaican fruit bat cells are not susceptible. www.biorxiv.org/content/10.1...

These data are complementary to reports of pathogenesis in bats challenged with ZIKV in vivo. Big congrats to my postdoc, Dr. Alexander Brown, and @annafagre.bsky.social who co-lead this study along with @ricardoriveroh.bsky.social @speranzalab.bsky.social @fviromics.bsky.social @viralemergence.org