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COVID-19 resulting from SARS-CoV-2 infection has presented significant challenges to global health over the past several years. Animal models are essential for studying the pathogenic mechanisms of SARS-CoV-2 and facilitating the development of therapeutic strategies. Transgenic hACE2 mouse models are widely used to explore the mechanisms responsible for severe and lethal COVID-19. However, current lethal transgenic mouse models are reported to die primarily from central nervous system infection, whereas in human patients, respiratory system infection is the primary cause of death. Moreover, earlier mouse models require the use of high-containment biosafety laboratories, which significantly limits SARS-CoV-2 studies and restricts broader experimental applications. Here, we established mouse models with systemic or lung-specific expression of the SARS-CoV-2 nucleocapsid (N) protein based on the K18-hACE2 KI mice. Both strains of mice are susceptible to SARS-CoV-2 ΔN/GFP-HBiT replicon delivery particles (RDPs), allowing efficient viral replication without producing infectious virions. Notably, lung-specific N-expressing mice exhibit only pulmonary infection, with lethality and pathological features closer to the clinical presentations of COVID-19. This RDP-infected mouse model enables the evaluation of anti-SARS-CoV-2 drugs, with infection phenotypes closely resembling those of wild-type SARS-CoV-2. Overall, this model offers a safer, increasingly convenient, and more universally applicable tool for SARS-CoV-2 research and antiviral therapy development.