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bioRxiv · 10.1101/2020.08.19.251249

A Human-Immune-System mouse model for COVID-19 research(DRAGA mouse: HLA-A2.HLA-DR4.Rag1KO.IL-2Rγc KO.NOD)

Brumeanu, T.-D.·Vir, P.·Shashikumar, S.·Karim, A. F.·Kar, S.·Chung, K. K.·Pratt, K. P.·Casares, S. A.
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Abstract

We report the first Human Immune System (HIS)-humanized mouse model ("DRAGA": HLA-A2.HLA-DR4.Rag1KO.IL-2R{gamma}cKO.NOD) for COVID-19 research. This mouse is reconstituted with human cord blood-derived, HLA-matched hematopoietic stem cells. It engrafts human epi/endothelial cells expressing the human ACE2 receptor for SARS-CoV-2 and TMPRSS2 serine protease co-localized on lung epithelia. HIS-DRAGA mice sustained SARS-CoV-2 infection, showing deteriorated clinical condition, replicating virus in the lungs, and human-like lung immunopathology including T-cell infiltrates, microthrombi and pulmonary sequelae. Among T-cell infiltrates, lung-resident (CD103+) CD8+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, indicating cytotoxic potential. Infected mice also developed antibodies against the SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathology and for testing the safety and efficacy of candidate vaccines and therapeutics.

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Brumeanu, T.-D., Vir, P., Shashikumar, S., Karim, A. F., Kar, S., Chung, K. K., Pratt, K. P., Casares, S. A.. 2020-08-20. A Human-Immune-System mouse model for COVID-19 research(DRAGA mouse: HLA-A2.HLA-DR4.Rag1KO.IL-2Rγc KO.NOD). https://doi.org/10.1101/2020.08.19.251249

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