Viral syncytia help SARS-CoV-2 evade interferon and antibodies

Viral syncytia evolve to resist interferon | Nature Communications

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Viral syncytia evolve to resist interferon

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Immune evasion SARS-CoV-2 Viral immune evasion

Abstract SARS-CoV-2, like many viruses, generates syncytia but the role of syncytia formation in viral evolution remains unknown. Using SARS-CoV-2 and SARS-CoV-2 Spike (S) replacement vesicular stomatitis (VSV), we show that S-mediated syncytia impair the antiviral effects of interferons in cultured cells, human lung cell cultures, and hACE2 transgenic mice. Amino acid substitutions that modulate syncytia formation in Delta- and Omicron-encoded S have parallel effects on viral interferon resistance. S-mediated syncytia compromise antibody-mediated virus neutralization in cultured cells. We recapitulate interferon and neutralizing antibody resistance in syncytia generated by the orthoreovirus p14 fusion-associated small transmembrane (FAST) protein in VSV, influenza virus, and seasonal coronavirus OC43 infections. These findings explain selection of SARS-CoV-2 fusogenic variants in humans and, more generally, the evolution of fusogenic viruses driven by adaptive and innate immunity.

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Acknowledgements We thank Zene Matsuda at the Institute of Medical Science (University of Tokyo) for providing dual split protein system: DSP 1-7 and DSP 8-11, and Chhing-Wen Chang (University of Massachusetts Chan Medical School) for providing A549plusC3 cell line, Sarah Anzick (RTB, NIAID) for NSG support, Bernard Lafont, Johnson Reed, and Nicole Lackemeyer (NIAID SARS-CoV-2 Virology Core BSL-3 facility), for superb support, training, and assistance. The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered works of the U.S. government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

Funding J.W.Y. discloses the research of this work is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [grant ZIAAI001320]. All other authors declare no relevant funding.

Author information Authors and Affiliations Cellular Biology Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA Tiansheng Li (李天胜), Zhe Hu (胡哲), James Gibbs, Ivan Kosik, Jaroslav Holly & Jonathan W. Yewdell

Laboratory of Respiratory Viral Diseases, Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA Insung Kang, Martina Kosikova, Zhiping Ye & Hang Xie

Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, USA Juan Ye (叶娟)

Texas Biomedical Research Institute, San Antonio, TX, USA Chengjin Ye & Luis Martinez-Sobrido

Microscopy and Imaging Core Facility, Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA Kazuyo Takeda

HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute (NCI), NIH, Frederick, MD, USA Guoli Shi (史国利) & Alex A. Compton

SARS-CoV-2 Virology Core Laboratory, Division of Intramural Research, National Institutes of Health, Bethesda, MD, USA Reed F. Johnson

AuthorsTiansheng Li (李天胜)View author publications Search author on:PubMed Google Scholar

Insung KangView author publications Search author on:PubMed Google Scholar

Juan Ye (叶娟)View author publications Search author on:PubMed Google Scholar

Zhe Hu (胡哲)View author publications Search author on:PubMed Google Scholar

James GibbsView author publications Search author on:PubMed Google Scholar

Chengjin YeView author publications Search author on:PubMed Google Scholar

Kazuyo TakedaView author publications Search author on:PubMed Google Scholar

Ivan KosikView author publications Search author on:PubMed Google Scholar

Guoli...

Viral syncytia help SARS-CoV-2 evade interferon and antibodies

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