Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2.HLA-DR4.Rag1KO.IL-2RγcKO.NOD) for COVID-19.
Hum Vaccin Immunother
; 18(5): 2048622, 2022 11 30.
Article
in English
| MEDLINE | ID: covidwho-1900981
ABSTRACT
We report a Human Immune System (HIS)-humanized mouse model ("DRAGA" HLA-A2.HLA-DR4.Rag1KO.IL-2 RγcKO.NOD) for COVID-19 research. DRAGA mice express transgenically HLA-class I and class-II molecules in the mouse thymus to promote human T cell development and human B cell Ig-class switching. When infused with human hematopoietic stem cells from cord blood reconstitute a functional human immune system, as well as human epi/endothelial cells in lung and upper respiratory airways expressing the human ACE2 receptor for SARS-CoV-2. The DRAGA mice were able to sustain SARS-CoV-2 infection for at least 25 days. Infected mice showed replicating virus in the lungs, deteriorating clinical condition, and human-like lung immunopathology including human lymphocyte infiltrates, microthrombi and pulmonary sequelae. Among the intra-alveolar and peri-bronchiolar lymphocyte infiltrates, human lung-resident (CD103+) CD8+ and CD4+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, suggesting anti-viral cytotoxic activity. Infected mice also mounted human IgG antibody responses to SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathological mechanisms and testing the safety and efficacy of candidate vaccines and therapeutics.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
HLA-DR4 Antigen
/
COVID-19
Type of study:
Prognostic study
Topics:
Long Covid
/
Vaccines
Limits:
Animals
/
Humans
Language:
English
Journal:
Hum Vaccin Immunother
Year:
2022
Document Type:
Article
Affiliation country:
21645515.2022.2048622
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