Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice

Ferran Tarrés-Freixas; Benjamin Trinité; Anna Pons-Grífols; Miguel Romero-Durana; Eva Riveira-Muñoz; Carlos Ávila-Nieto; Mónica Pérez; Mónica Pérez; Edurne Garcia-Vidal; Daniel Perez-Zsolt; Jordana Muñoz-Basagoiti; Dàlia Raïch-Regué; Nuria Izquierdo-Useros; Nuria Izquierdo-Useros; Nuria Izquierdo-Useros; Cristina Andrés; Andrés Antón; Tomàs Pumarola; Ignacio Blanco; Marc Noguera-Julián; Marc Noguera-Julián; Marc Noguera-Julián; Victor Guallar; Victor Guallar; Rosalba Lepore; Alfonso Valencia; Alfonso Valencia; Victor Urrea; Júlia Vergara-Alert; Júlia Vergara-Alert; Bonaventura Clotet; Bonaventura Clotet; Ester Ballana; Ester Ballana; Jorge Carrillo; Jorge Carrillo; Jorge Carrillo; Joaquim Segalés; Joaquim Segalés; Julià Blanco; Julià Blanco; Julià Blanco; Julià Blanco

Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice

2022

The emerging SARS-CoV-2 variants of concern (VOCs) may display enhanced transmissibility, more severity and/or immune evasion; however, the pathogenesis of these new VOCs in experimental SARS-CoV-2 models or the potential infection of other animal species is not completely understood. Here we infected K18-hACE2 transgenic mice with B.1, B.1.351/Beta, B.1.617.2/Delta and BA.1.1/Omicron isolates and demonstrated heterogeneous infectivity and pathogenesis. B.1.351/Beta variant was the most pathogenic, while BA.1.1/Omicron led to lower viral RNA in the absence of major visible clinical signs. In parallel, we infected wildtype (WT) mice and confirmed that, contrary to B.1 and B.1.617.2/Delta, B.1.351/Beta and BA.1.1/Omicron can infect them. Infection in WT mice coursed without major clinical signs and viral RNA was transient and undetectable in the lungs by day 7 post-infection. In silico modeling supported these findings by predicting B.1.351/Beta receptor binding domain (RBD) mutations result in an increased affinity for both human and murine ACE2 receptors, while BA.1/Omicron RBD mutations only show increased affinity for murine ACE2.

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