A human-ACE2 knock-in mouse model for SARS-CoV-2 infection recapitulates respiratory disorders but avoids neurological disease associated with the transgenic K18-hACE2 model

K18-hACE2 mice express high levels of the human protein angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and are therefore susceptible to infection by this virus. These animals have been crucial to understanding viral pathogenesis...

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Authors: Pons-Grífols, Anna|||0000-0002-8402-3941, Tarrés-Freixas, Ferran|||0000-0002-1569-0126, Pérez, Mònica, Riveira Muñoz, Eva|||0000-0002-6396-1162, Raïch-Regué, Dàlia|||0000-0001-7656-5700, Perez-Zsolt, Daniel|||0000-0003-4192-7622, Muñoz-Basagoiti, Jordana|||0000-0002-0384-5928, Tondelli, Barbara, Pradenas, Edwards|||0000-0001-5162-8920, Izquierdo Useros, Nuria|||0000-0002-1039-1821, Capdevila, Sara, Vergara-Alert, Júlia|||0000-0001-7484-444X, Urrea, Víctor|||0000-0002-2577-856X, Carrillo, Jorge|||0000-0003-0221-5948, Ballana, Ester|||0000-0002-5215-7363, Forrow, Stephen, Clotet Sala, Bonaventura|||0000-0003-3232-4598, Segalés Coma, Joaquim|||0000-0002-1539-7261, Trinité, Benjamin|||0000-0003-3809-042X, Blanco, Julià|||0000-0002-2225-0217
Format: article
Publication Date:2025
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:319646
Online Access:https://ddd.uab.cat/record/319646
https://dx.doi.org/urn:doi:10.1128/mbio.00720-25
Access Level:Open access
Keyword:Animal model
Lung inflammation
Lung damage
Neuroinvasion
Post-covid condition
Description
Summary:K18-hACE2 mice express high levels of the human protein angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and are therefore susceptible to infection by this virus. These animals have been crucial to understanding viral pathogenesis and to testing coronavirus disease 2019 (COVID-19) vaccines and antiviral drugs. However, K18-hACE2 often dies after infection with initial SARS-CoV-2 variants, likely due to a massive brain infection that does not occur in humans. Here, we used a technology known as knock-in (KI) that allows for the targeted insertion of a gene into a mouse, and we have generated a new human ACE2 (hACE2) mouse. We have characterized this new animal model demonstrating that, upon challenge with SARS-CoV-2, the virus replicates in the respiratory tract, damaging lung tissue and causing inflammation. In contrast to K18-hACE2 mice, only limited or no brain infection could be detected in this new model. After 14 days, most animals recovered from the infection, although lung tissue lesions were still observed. This new model could be instrumental for the study of specific disease aspects such as post-COVID-19 condition, sequelae, and susceptibility to reinfection.

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