Variant mutation in SARS-CoV-2 nucleocapsid enhances viral infection via altered genomic encapsidation

Author:

Kubinski Hannah C.,Despres Hannah W.ORCID,Johnson Bryan A.,Schmidt Madaline M.ORCID,Jaffrani Sara A.,Mills Margaret G.ORCID,Lokugamage Kumari,Dumas Caroline M.,Shirley David J.,Estes Leah K.,Pekosz AndrewORCID,Crothers Jessica W.,Roychoudhury PavitraORCID,Greninger Alexander L.ORCID,Jerome Keith R.,Di Genova Bruno MartorelliORCID,Walker David H.,Ballif Bryan A.,Ladinsky Mark S.ORCID,Bjorkman Pamela J.,Menachery Vineet D.ORCID,Bruce Emily A.ORCID

Abstract

ABSTRACTThe evolution of SARS-CoV-2 variants and their respective phenotypes represents an important set of tools to understand basic coronavirus biology as well as the public health implications of individual mutations in variants of concern. While mutations outside of Spike are not well studied, the entire viral genome is undergoing evolutionary selection, particularly the central disordered linker region of the nucleocapsid (N) protein. Here, we identify a mutation (G215C), characteristic of the Delta variant, that introduces a novel cysteine into this linker domain, which results in the formation of a disulfide bond and a stable N-N dimer. Using reverse genetics, we determined that this cysteine residue is necessary and sufficient for stable dimer formation in a WA1 SARS-CoV-2 background, where it results in significantly increased viral growth bothin vitroandin vivo. Finally, we demonstrate that the N:G215C virus packages more nucleocapsid per virion and that individual virions are larger, with elongated morphologies.

Publisher

Cold Spring Harbor Laboratory

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