@article{ec94beecdda746d29b9c85f446ce4dd0,
title = "Determinants and Mechanisms of the Low Fusogenicity and High Dependence on Endosomal Entry of Omicron Subvariants",
abstract = "The rapid spread and strong immune evasion of the SARS-CoV-2 Omicron subvariants has raised serious concerns for the global COVID-19 pandemic. These new variants exhibit generally reduced fusogenicity and increased endosomal entry pathway utilization compared to the ancestral D614G variant, the underlying mechanisms of which remain elusive. Here, we show that the C-terminal S1 mutations of the BA.1.1 subvariant, H655Y and T547K, critically govern the low fusogenicity of Omicron. Notably, H655Y also dictates the enhanced endosome entry pathway utilization. Mechanistically, T547K and H655Y likely stabilize the spike trimer conformation as suggested by increased molecular interactions in structural modeling and enhanced S1 shedding of their reversion mutants K547T and Y655H in viral producer cells. Importantly, the H655Y mutation also determines the low fusogenicity and enhanced dependence on the endosomal entry pathway of other Omicron subvariants, including BA.2, BA.2.12.1, BA.4/5, and BA.2.75. Together, these results uncover mechanisms governing Omicron subvariant entry and provide insights into altered Omicron tissue tropism and pathogenesis.",
keywords = "endosomal entry, furin cleavage, fusogenicity, H655Y, Omicron subvariants",
author = "Panke Qu and Evans, {John P.} and Chaitanya Kurhade and Cong Zeng and Zheng, {Yi Min} and Kai Xu and Shi, {Pei Yong} and Xuping Xie and Liu, {Shan Lu}",
note = "Funding Information: S.-L.L. was supported by a fund provided by an anonymous private donor to The Ohio State University (OSU). S.-L.L. was also supported by the National Cancer Institute of the NIH under award no. U54CA260582. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. J.P.E. was supported by a Glenn Barber Fellowship from the Ohio State University College of Veterinary Medicine. K.X. was supported by the Ohio State University Comprehensive Cancer Center and a Path to K grant through the Ohio State University Center for Clinical & Translational Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of the university or the Center for Clinical & Translational Science. P.-Y.S. was supported by NIH grants HHSN272201600013C and U01AI151801 and awards from the Sealy & Smith Foundation, the Kleberg Foundation, the John S. Dunn Foundation, the Amon G. Carter Foundation, the Summerfield Robert Foundation, and Edith and Robert Zinn. We have no competing interests to disclose. Publisher Copyright: {\textcopyright} 2023 Qu et al.",
year = "2023",
month = jan,
doi = "10.1128/mbio.03176-22",
language = "English (US)",
volume = "14",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "1",
}