2026-04-14T02:33:30Zhttps://recercat.cat/oai/request

oai:recercat.cat:20.500.12327/48092026-03-07T00:33:51Zcom_2072_4428com_2072_4427col_2072_487898

00925njm 22002777a 4500 dc Pons-Grífols, Anna author Tarrés Freixas, Ferran author Pérez Maíllo, Mónica author Riveira-Muñoz, Eva author Raïch-Regué, Dàlia author Perez-Zsolt, Daniel author Muñoz Basagoiti, Jordana author Tondelli, Barbara author Pradenas, Edwards author Izquierdo-Useros, Nuria author Capdevila, Sara author Vergara-Alert, Júlia author Urrea, Victor author Carrillo, Jorge author Ballana, Ester author Forrow, Stephen author Clotet, Bonaventura author Segalés, Joaquim author Trinité, Benjamin author Blanco, Julià author 2025-04-24 Animal models have been instrumental in elucidating the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and in testing coronavirus disease 2019 (COVID-19) vaccines and therapeutics. Wild-type (WT) mice are not susceptible to many SARS-CoV-2 variants, and therefore, transgenic K18-hACE2 mice have emerged as a standard model system. However, this model is characterized by a severe disease, particularly associated with neuroinfection, which leads to early humane endpoint euthanasia. Here, we established a novel knock-in (KI) mouse model by inserting the original K18-hACE2 transgene into the collagen type I alpha chain (COL1A1) locus using a recombinase-mediated cassette exchange (RMCE) system. Once the Col1a1-K18-hACE2 mouse colony was established, animals were challenged with a B.1 SARS-CoV-2 (D614G) isolate and were monitored for up to 14 days. Col1a1-K18-hACE2 mice exhibited an initial weight loss similar to the K18-hACE2 transgenic model but did not develop evident neurologic clinical signs. The majority of Col1a1-K18-hACE2 mice did not reach the pre-established humane endpoint, showing a progressive weight gain 9 days postinfection (dpi). Importantly, despite this apparent milder pathogenicity of the virus in this mouse model compared to the K18-hACE2 transgenic model, high levels of viral RNA were detected in the lungs, oropharyngeal swab, and nasal turbinates. Moreover, the remaining lesions and inflammation in the lungs were still observed 14 dpi. In contrast, although low-level viral RNA could be detected in a minority of Col1a1-K18-hACE2 animals, no brain lesions were observed at any timepoint. Overall, Col1a1-K18-hACE2 mice constitute a new model for investigating SARS-CoV-2 pathogenesis and treatments, with potential implications for studying long-term COVID-19 sequelae. Pons-Grífols, Anna, Ferran Tarrés-Freixas, Mònica Pérez, Eva Riveira-Muñoz, Dàlia Raïch-Regué, Daniel Perez-Zsolt, Jordana Muñoz-Basagoiti, et al. 2025. “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.” mBio 16(5): e00720-2. https://doi.org/10.1128/mbio.00720-25. 2161-2129 http://hdl.handle.net/20.500.12327/4809 https://doi.org/10.1128/mbio.00720-25 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