Application of the humanized mouse model in research into SARS-CoV-2 infection (Review)

The coronavirus disease 2019 (COVID-19) pandemic triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a profound impact on global public health. The complexity of its pathogenic mechanisms and host interactions urgently requires high-fidelity animal models to support research. Humanized mouse models break the species barrier through gene editing and immune reconstitution technologies, providing a key tool to simulate human infection characteristics and pathological processes. A number of studies have reported the application of humanized mouse models in the fields of COVID-19 research, such as SARS-CoV-2 pathogenesis, anti-SARS-CoV-2 drug discovery and vaccine development, etc. The present review aimed to systematically document the latest advances in the application of humanized mouse models based on different construction strategies, such as receptor humanization, immune system humanization and composite humanization. These models have not only elucidated the pathogenicity differences and immune escape mechanisms of SARS-CoV-2 variants, but have also validated the efficacy of broad-spectrum anti-SARS-CoV-2 strategies, including angiotensin-converting enzyme 2-targeted therapies, antibody cocktail regimens and mucosal vaccines. Additionally, humanized mouse models have played a pivotal role in investigating the mechanisms underlying long COVID. By revealing the multi-system pathogenic mechanisms of pulmonary fibrosis, neurodegeneration and intestinal microbiota dysregulation, these models provide a theoretical foundation for the development of targeted intervention strategies.