Brumeanu Teodor-D, Vir Pooja, Karim Ahmad Faisal, Kar Swagata, Benetiene Dalia, Lok Megan, Greenhouse Jack, Putmon-Taylor Tammy, Kitajewski Christopher, Chung Kevin K, Pratt Kathleen P, Casares Sofia A
Uniformed Services University of the Health Sciences, Department of Medicine, Division of Immunology, Bethesda, MD 20814, U.S.A.
Bioqual Inc., Rockville, MD 20852, U.S.A.
bioRxiv. 2021 Jan 29:2020.08.19.251249. doi: 10.1101/2020.08.19.251249.
We report the first Human Immune System (HIS)-humanized mouse model ("DRAGA": HLA-A2.HLA-DR4.Rag1KO.IL-2RγcKO.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 human model for studying SARS-CoV-2 immunopathology and for testing the safety and efficacy of candidate vaccines and therapeutics.
我们报告了首个用于新冠病毒（COVID-19）研究的人免疫系统（HIS）人源化小鼠模型（“DRAGA”：HLA-A2.HLA-DR4.Rag1KO.IL-2RγcKO.NOD）。该小鼠用人脐带血来源、HLA匹配的造血干细胞进行重建。它植入了表达人血管紧张素转换酶2（ACE2）受体以用于严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的人上皮/内皮细胞以及共定位于肺上皮的跨膜丝氨酸蛋白酶2（TMPRSS2）。HIS-DRAGA小鼠维持了SARS-CoV-2感染，表现出临床状况恶化，在肺部复制病毒，以及出现类似人类的肺免疫病理学变化，包括T细胞浸润、微血栓和肺部后遗症。在T细胞浸润中，驻留在肺中的（CD103）CD8 T细胞被隔离在上皮（CD326）肺微环境中，并分泌颗粒酶B和穿孔素，表明具有细胞毒性潜力。受感染的小鼠还产生了针对SARS-CoV-2病毒蛋白的抗体。因此，HIS-DRAGA小鼠作为研究SARS-CoV-2免疫病理学以及测试候选疫苗和治疗方法的安全性和有效性的替代人类模型显示出独特优势。
