SARS-CoV-2 variant of concern fitness and adaptation in primary human airway epithelia
Rita M. Meganck,
Caitlin E. Edwards,
Michael L. Mallory,
Rhianna E. Lee,
Hong Dang,
Alexis B. Bailey,
Jason A. Wykoff,
Samuel C. Gallant,
Deanna R. Zhu,
Boyd L. Yount,
Takafumi Kato,
Kendall M. Shaffer,
Satoko Nakano,
Anne Marie Cawley,
Vishwaraj Sontake,
Jeremy R. Wang,
Robert S. Hagan,
Melissa B. Miller,
Purushothama Rao Tata,
Scott H. Randell,
Longping V. Tse,
Camille Ehre,
Kenichi Okuda,
Richard C. Boucher,
Ralph S. Baric
Affiliations
Rita M. Meganck
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Caitlin E. Edwards
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Michael L. Mallory
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Rhianna E. Lee
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Hong Dang
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Alexis B. Bailey
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Jason A. Wykoff
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Samuel C. Gallant
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Deanna R. Zhu
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Boyd L. Yount
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Takafumi Kato
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Kendall M. Shaffer
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Satoko Nakano
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Anne Marie Cawley
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Vishwaraj Sontake
Department of Cell Biology, Duke University, Durham, NC 27710, USA
Jeremy R. Wang
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Robert S. Hagan
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Division of Pulmonary Diseases and Critical Care Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Melissa B. Miller
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Purushothama Rao Tata
Department of Cell Biology, Duke University, Durham, NC 27710, USA
Scott H. Randell
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Longping V. Tse
Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, MO 63104, USA
Camille Ehre
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Kenichi Okuda
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Richard C. Boucher
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Ralph S. Baric
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Corresponding author
Summary: The severe acute respiratory syndrome coronavirus 2 pandemic is characterized by the emergence of novel variants of concern (VOCs) that replace ancestral strains. Here, we dissect the complex selective pressures by evaluating variant fitness and adaptation in human respiratory tissues. We evaluate viral properties and host responses to reconstruct forces behind D614G through Omicron (BA.1) emergence. We observe differential replication in airway epithelia, differences in cellular tropism, and virus-induced cytotoxicity. D614G accumulates the most mutations after infection, supporting zoonosis and adaptation to the human airway. We perform head-to-head competitions and observe the highest fitness for Gamma and Delta. Under these conditions, RNA recombination favors variants encoding the B.1.617.1 lineage 3′ end. Based on viral growth kinetics, Alpha, Gamma, and Delta exhibit increased fitness compared to D614G. In contrast, the global success of Omicron likely derives from increased transmission and antigenic variation. Our data provide molecular evidence to support epidemiological observations of VOC emergence.
