SARS-CoV-2 spike D614G change enhances replication and transmission

• Published in: Nature (London) Vol. 592; no. 7852; pp. 122 - 127
• Main Authors: Zhou, Bin, Thao, Tran Thi Nhu, Hoffmann, Donata, Taddeo, Adriano, Ebert, Nadine, Labroussaa, Fabien, Pohlmann, Anne, King, Jacqueline, Steiner, Silvio, Kelly, Jenna N., Portmann, Jasmine, Halwe, Nico Joel, Ulrich, Lorenz, Trüeb, Bettina Salome, Fan, Xiaoyu, Hoffmann, Bernd, Wang, Li, Thomann, Lisa, Lin, Xudong, Stalder, Hanspeter, Pozzi, Berta, de Brot, Simone, Jiang, Nannan, Cui, Dan, Hossain, Jaber, Wilson, Malania M., Keller, Matthew W., Stark, Thomas J., Barnes, John R., Dijkman, Ronald, Jores, Joerg, Benarafa, Charaf, Wentworth, David E., Thiel, Volker, Beer, Martin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2021; Nature Publishing Group
• Subjects: 38; 45/77; 59; 631/326/596/4130; 64; 64/110; 692/699/255/2514; ACE2; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; Animal models; Animals; Binding; Bronchi - cytology; Bronchi - virology; Cell culture; Cell Line; Cell surface; Cells, Cultured; Competitive advantage; Coronaviruses; COVID-19; COVID-19 - epidemiology; COVID-19 - transmission; COVID-19 - virology; Cricetinae; Disease Models, Animal; Disease transmission; Epithelial Cells - virology; Female; Ferrets - virology; Founder Effect; Gene Knock-In Techniques; Genetic Fitness; Glycoproteins; Humanities and Social Sciences; Humans; Infections; Male; Mesocricetus; Mice; multidisciplinary; Mutation; Nasal Mucosa - cytology; Nasal Mucosa - virology; Pandemics; Peptidyl-dipeptidase A; Protein Binding; Proteins; Receptors, Coronavirus - metabolism; Replication; RNA, Viral - analysis; SARS-CoV-2 - genetics; SARS-CoV-2 - metabolism; SARS-CoV-2 - pathogenicity; SARS-CoV-2 - physiology; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike glycoprotein; Spike Glycoprotein, Coronavirus - genetics; Substitutes; Viral diseases; Virus Replication - genetics; Viruses
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03361-1

During the evolution of SARS-CoV-2 in humans, a D614G substitution in the spike glycoprotein (S) has emerged; virus containing this substitution has become the predominant circulating variant in the COVID-19 pandemic 1 . However, whether the increasing prevalence of this variant reflects a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains unknown. Here we use isogenic SARS-CoV-2 variants to demonstrate that the variant that contains S(D614G) has enhanced binding to the human cell-surface receptor angiotensin-converting enzyme 2 (ACE2), increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a human ACE2 knock-in mouse model, and markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Our data show that the D614G substitution in S results in subtle increases in binding and replication in vitro, and provides a real competitive advantage in vivo—particularly during the transmission bottleneck. Our data therefore provide an explanation for the global predominance of the variant that contains S(D614G) among the SARS-CoV-2 viruses that are currently circulating. A SARS-CoV-2 variant containing a D614G substitution in the spike protein shows enhanced binding to human ACE2, increased replication in human cell cultures and a competitive advantage in animal models of infection.