Omicron subvariant BA.5 efficiently infects lung cells

• Published in: Nature communications Vol. 14; no. 1; pp. 3500 - 11
• Main Authors: Hoffmann, Markus, Wong, Lok-Yin Roy, Arora, Prerna, Zhang, Lu, Rocha, Cheila, Odle, Abby, Nehlmeier, Inga, Kempf, Amy, Richter, Anja, Halwe, Nico Joel, Schön, Jacob, Ulrich, Lorenz, Hoffmann, Donata, Beer, Martin, Drosten, Christian, Perlman, Stanley, Pöhlmann, Stefan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 38/70; 42/44; 631/326/596/2557; 631/326/596/4130; 64/60; Animals; Attenuation; Cell fusion; COVID-19; Evolution; Female; Females; Ferrets; Humanities and Social Sciences; Lung; Lungs; Mice; Mice, Inbred BALB C; multidisciplinary; Nose; Pathogenicity; Pathogens; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Viral diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39147-4

The SARS-CoV-2 Omicron subvariants BA.1 and BA.2 exhibit reduced lung cell infection relative to previously circulating SARS-CoV-2 variants, which may account for their reduced pathogenicity. However, it is unclear whether lung cell infection by BA.5, which displaced these variants, remains attenuated. Here, we show that the spike (S) protein of BA.5 exhibits increased cleavage at the S1/S2 site and drives cell-cell fusion and lung cell entry with higher efficiency than its counterparts from BA.1 and BA.2. Increased lung cell entry depends on mutation H69Δ/V70Δ and is associated with efficient replication of BA.5 in cultured lung cells. Further, BA.5 replicates in the lungs of female Balb/c mice and the nasal cavity of female ferrets with much higher efficiency than BA.1. These results suggest that BA.5 has acquired the ability to efficiently infect lung cells, a prerequisite for causing severe disease, suggesting that evolution of Omicron subvariants can result in partial loss of attenuation. The Omicron variant is partially attenuated, likely because it fails to efficiently infect lung cells. Here, Hoffmann et. al. show that this defect can be lost during Omicron evolution as demonstrated for the subvariant BA.5 that robustly infects lung cells in vitro and in vivo.