GSE175900
Humanized mice for investigating SARS-CoV-2 lung infection and associated human immune responses
There is an urgent need for animal models of COVID-19 to study immunopathogenesis and test therapeutic intervenes. In this study we showed that NSG mice engrafted with human lung (HL) tissue (NSG-L) could be infected efficiently by SARS-CoV-2, and that live viruses capable of infecting human Vero cells were found in the HL grafts and multiple organs from infected NSG-L mice. RNA-seq examination identified a series of differentially expressed genes, which are enriched in viral defense responses, chemotaxis, interferon stimulation, and pulmonary fibrosis between HL grafts from infected and control NSG-L mice. Furthermore, when infecting humanized mice with human immune system (HIS) and autologous HL grafts (HISL mice), the mice had bodyweight loss and hemorrhage in HL grafts, which were not observed in immunodeficient NSG-L mice, indicating the development of anti-viral immune responses in these mice. In support of this possibility, the infected HISL mice showed bodyweight recovery and lack of detectable live viruses at the later time. These results demonstrate that NSG-L and HISL mice are susceptible to SARS-CoV-2 infection, offering a useful in vivo model for studying SARS-CoV-2 infection and the associated immune response and immunopathology, and testing anti-SARS-CoV-2 therapies. Overall design: NSG mice were implanted subcutaneously with human lung (HL) tissue, and subjected to infection via intra-HL injection of SARS-CoV-2 or PBS 6-8 weeks later. Human lung samples were harvested from uninfected or 5-day and 21-day infected NSG-L mice and analyzed for whole-transcriptome profiling by RNA-seq.