Molecular basis of pathogenicity of the recently emerged FCoV-23 coronavirus

Tortorici, M. A.; Choi, A.; Gibson, C.; Lee, J.; Brown, J. T.; Stewart, C.; Joshi, A.; Harari, S.; Willoughby, I.; Treichel, C.; Leif, E.; Bloom, J. D.; King, N. P.; Tait-Burkard, C.; Whittaker, G. R.; Veesler, D.

doi:10.1101/2024.08.25.607996

bioRxiv · 10.1101/2024.08.25.607996

Molecular basis of pathogenicity of the recently emerged FCoV-23 coronavirus

Tortorici, M. A.·Choi, A.·Gibson, C.·Lee, J.·Brown, J. T.·Stewart, C.·Joshi, A.·Harari, S.·Willoughby, I.·Treichel, C.·Leif, E.·Bloom, J. D.·King, N. P.·Tait-Burkard, C.·Whittaker, G. R.·Veesler, D.

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Abstract

The ability of coronaviruses to recombine and cross species barriers affects human and animal health globally and is a pandemic threat. FCoV-23 is a recently emerged, highly pathogenic recombinant coronavirus responsible for a widespread outbreak of feline infectious peritonitis (FIP) likely linked to in-host viral evolution. Here, we report cryoEM structures of two FCoV-23 spike (S) isoforms explaining that the in-host loss of domain 0 observed in clinical samples enhances entry into cells and fusogenicity by facilitating protease access, leading to biotype switching and lethality. We show that FCoV-23 can use several aminopeptidase N (APN) orthologs as receptors and reveal the molecular determinants of receptor species tropism, including a glycan modulating human receptor utilization. We define antigenic relationships among alphacoronaviruses infecting humans and other mammalian species and identify a cross-reactive alphacoronavirus monoclonal antibody inhibiting FCoV-23 pseudovirus entry, paving the way for vaccine and therapeutic development targeting this highly pathogenic virus.

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Tortorici, M. A., Choi, A., Gibson, C., Lee, J., Brown, J. T., Stewart, C., Joshi, A., Harari, S., Willoughby, I., Treichel, C., Leif, E., Bloom, J. D., King, N. P., Tait-Burkard, C., Whittaker, G. R., Veesler, D.. 2024-08-26. Molecular basis of pathogenicity of the recently emerged FCoV-23 coronavirus. https://doi.org/10.1101/2024.08.25.607996

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