TY - JOUR
T1 - A Human-Immune-System (HIS) humanized mouse model (DRAGA
T2 - HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19
AU - Brumeanu, Teodor-D
AU - Vir, Pooja
AU - Karim, Ahmad Faisal
AU - Kar, Swagata
AU - Benetiene, Dalia
AU - Lok, Megan
AU - Greenhouse, Jack
AU - Putmon-Taylor, Tammy
AU - Kitajewski, Christopher
AU - Chung, Kevin K
AU - Pratt, Kathleen P
AU - Casares, Sofia A
PY - 2021/1/29
Y1 - 2021/1/29
N2 - 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
in vivo human model for studying SARS-CoV-2 immunopathology and for testing the safety and efficacy of candidate vaccines and therapeutics.
AB - 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
in vivo human model for studying SARS-CoV-2 immunopathology and for testing the safety and efficacy of candidate vaccines and therapeutics.
U2 - 10.1101/2020.08.19.251249
DO - 10.1101/2020.08.19.251249
M3 - Article
C2 - 32839773
JO - bioRxiv : the preprint server for biology
JF - bioRxiv : the preprint server for biology
ER -