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, Edurne García-Vidal, Daniel Perez‐Zsolt, Jordana Muñoz‐Basagoiti, Dàlia Raϊch‐Regué, Nuria Izquierdo‐Useros, Cristina Andrés, Andrés Antón, Tomàs Pumarola, Ignacio Blanco, Marc Noguera-Julián, Vı́ctor Guallar, Rosalba Lepore, Alfonso Valencia, Víctor Urrea, Júlia Vergara‐Alert, Bonaventura Clotet, Ester Ballana, Jorge Carrillo, Joaquím Segalés, Julià Blanco
Abstract
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.