Journal
THERANOSTICS
Volume 11, Issue 13, Pages 6607-6615Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.58321
Keywords
SARS-CoV-2; infection; human lung; xenograft; humanized mouse model
Categories
Funding
- National Science and Technology Major Project of Infectious Diseases [2017ZX10304402002003]
- National Science and Technology Major Projects for Major New Drugs Innovation and Development [2018ZX09711003005003]
- National Natural Science Foundation of China [82041038]
- Science and Technology Project of Fujian Province [2020YZ014001]
- Science and Technology Project of Xiamen City [3502Z2020YJ01]
- CAMS Innovation Fund for Medical Sciences [2019RU022]
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This study utilized a humanized mouse model with human lung xenografts to investigate SARS-CoV-2 infection. The results showed that the human lung xenografts closely resembled normal human lung structure, supported efficient replication and spread of SARS-CoV-2, caused severe lung damage, and induced a strong pro-inflammatory response. Treatment with IFN-alpha effectively inhibited viral replication in the lung xenografts. This model proves to be a valuable tool for studying SARS-CoV-2 lung infection pathogenesis and evaluating potential antiviral therapies.
SARS-CoV-2 infection, which is responsible for the current COVID-19 pandemic, can cause life-threatening pneumonia, respiratory failure and even death. Characterizing SARS-CoV-2 pathogenesis in primary human target cells and tissues is crucial for developing vaccines and therapeutics. However, given the limited access to clinical samples from COVID-19 patients, there is a pressing need for in vitro/in vivo models to investigate authentic SARS-CoV-2 infection in primary human lung cells or tissues with mature structures. The present study was designed to evaluate a humanized mouse model carrying human lung xenografts for SARS-CoV-2 infection in vivo. Methods: Human fetal lung tissue surgically grafted under the dorsal skin of SCID mice were assessed for growth and development after 8 weeks. Following SARS-CoV-2 inoculation into the differentiated lung xenografts, viral replication, cell-type tropism and histopathology of SARS-CoV-2 infection, and local cytokine/chemokine expression were determined over a 6-day period. The effect of IFN-alpha treatment against SARS-CoV-2 infection was tested in the lung xenografts. Results: Human lung xenografts expanded and developed mature structures closely resembling normal human lung. SARS-CoV-2 replicated and spread efficiently in the lung xenografts with the epithelial cells as the main target, caused severe lung damage, and induced a robust pro-inflammatory response. IFN-alpha treatment effectively inhibited SARS-CoV-2 replication in the lung xenografts. Conclusions: These data support the human lung xenograft mouse model as a useful and biological relevant tool that should facilitate studies on the pathogenesis of SARS-CoV-2 lung infection and the evaluation of potential antiviral therapies.
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