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: COVID-19; DRAGA mice; Human immune system; SARS-CoV-2; human antibodies; human lung-resident CD8 T cells; humanized mice; lung immunopathology.
【저자키워드】 COVID-19, SARS-CoV-2, humanized mice, DRAGA mice, Human immune system, human antibodies, human lung-resident CD8 T cells, lung immunopathology., 【초록키워드】 Efficacy, Therapeutics, T cells, SARS-COV-2 infection, Human, lung, Viral proteins, Proteins, CD4, CD8, lung immunopathology, immune, Anti-viral, B cell, lymphocyte, T cell, Cord blood, IgG antibody, mice, response, Lungs, Hematopoietic stem cell, in vivo, epithelial, mechanism, Blood, granzyme B, Human immune system, switching, microthrombi, candidate vaccine, human ACE2 receptor, clinical condition, perforin, Express, COVID-19 research, replicating virus, surrogate, cytotoxic activity, humanized, System, Cell, SARS-CoV-2 viral, functional, unique, promote, expressing, immunopathological, infused, intra-alveolar, mounted, secreted, upper respiratory airway, 【제목키워드】 humanized,