Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2.HLA-DR4.Rag1KO.IL-2RγcKO.NOD) for COVID-19

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.

Assessment of Immunogenic and Antigenic Properties of Recombinant Nucleocapsid Proteins of Five SARS-CoV-2 Variants in a Mouse Model

“…As the mouse major histocompatibility complex (MHC) is known to be remarkably different from the human leukocyte antigen (HLA) system [ 48 ], our animal model is not applicable for assessment of T-cell-mediated immune responses triggered via N-protein immunization. To study T-cell-involving reactions with maximal approximation to the human organism, use of HLA transgenic humanized mouse models is required [ 49 , 50 ].…”

The NOD Mouse Beyond Autoimmune Diabetes

“…Additional NOD mouse models are constantly being created to enhance human cell engraftment or to study specific diseases (200)(201)(202)(203)(204)(205)(206). For instance, the Human Immune System (HIS)-DRAGA (HLA-A2.HLA-DR4.Rag1 -/-.IL-2Rgc -/-.NOD) mouse, grafted with human epithelial cells expressing the human angiotensinconverting enzyme 2 (hACE2) receptor in their lungs, was generated for COVID-19 research (207). Following immune reconstitution with human HLA-matched hematopoietic stem cells and intranasal infection with SARS-CoV-2, the HIS-DRAGA mouse exhibits T cell infiltration in the lungs and develops the different forms of severity of COVID-19 disease, as seen in the human population (207).…”

“…For instance, the Human Immune System (HIS)-DRAGA (HLA-A2.HLA-DR4.Rag1 -/-.IL-2Rgc -/-.NOD) mouse, grafted with human epithelial cells expressing the human angiotensinconverting enzyme 2 (hACE2) receptor in their lungs, was generated for COVID-19 research (207). Following immune reconstitution with human HLA-matched hematopoietic stem cells and intranasal infection with SARS-CoV-2, the HIS-DRAGA mouse exhibits T cell infiltration in the lungs and develops the different forms of severity of COVID-19 disease, as seen in the human population (207). The HIS-DRAGA mouse strain provides an important model for studying SARS-CoV-2 infection, as well as the immune responses generated against this virus, and can be used to test potential therapeutics and vaccines (207).…”

“…Following immune reconstitution with human HLA-matched hematopoietic stem cells and intranasal infection with SARS-CoV-2, the HIS-DRAGA mouse exhibits T cell infiltration in the lungs and develops the different forms of severity of COVID-19 disease, as seen in the human population (207). The HIS-DRAGA mouse strain provides an important model for studying SARS-CoV-2 infection, as well as the immune responses generated against this virus, and can be used to test potential therapeutics and vaccines (207).…”

After the virus has cleared—Can preclinical models be employed for Long COVID research?

“…Other potential SARS-CoV-2 mouse models include humanized mice or collaborative cross mice [ 121 ]. Human immune system (HIS)-humanized mice have components of the human immune system, express hACE2 and TMPRSS2 serine protease on lung epithelia, and are susceptible to SARS-CoV-2 [ 122 ]. On the other hand, MISTRG6 humanized mice in combination with AAV delivery of hACE2 to the lungs have been used to study post-acute COVID-19 [ 123 ].…”