A Human-Immune-System mouse model for COVID-19 research (DRAGA mouse: HLA-A2.HLA-DR4.Rag1KO.IL-2Rγc KO.NOD)

Brumeanu, Teodor-D; Vir, Pooja; Shashikumar, Soumya; Karim, Ahmad Faisal; Kar, Swagata; Chung, Kevin K.; Pratt, Kathleen P.; Casares, Sofia

The current SARS-CoV-2 pandemic is accompanied by high morbidity and mortality rates, and there is a compelling need for effective vaccines and therapeutic agents to lessen the severity of COVID-19 disease. Appropriate animal models are essential for testing of vaccines and therapeutics and for mechanistic studies of infection and the host response. The Spike (S) protein of SARS-COV-2 has a high affinity for the human ACE2 receptor, which is expressed on multiple cell types including alveolar epithelial and vascular endothelial cells. Wild-type mice are not susceptible to developing coronavirus-mediated diseases. Accordingly, several human (h)ACE2 transgenic mouse models have been developed for coronavirus research. However, these mice have failed to closely mimic important aspects of the human immunopathological responses to SARS-CoV-2. We report herein that DRAGA (HLA-A2.HLA-DR4.Rag1KO.IL-2Rγc KO.NOD) mice infused with human hematopoietic stem cells from cord blood reconstitute a fully functional human immune system, as well as engraft human epithelial and endothelial cells, sustain SARS-CoV-2 infection, and develop severe COVID-19-like symptoms. In pilot experiments, infected mice developed parenchymal and epithelial lung infiltrations with granzyme B(+) and perforin(+) CD8(+) T cells and alveolar CD61(+) microthrombi, mimicking human immunopathological responses to SARS-CoV-2. We propose the DRAGA mouse as a novel pre-clinical tool for studying COVID-19 immunopathology and human immune responses to SARS-CoV-2, including events leading to the cytokine storm and coagulopathies, as well as for testing of candidate vaccines and therapeutics.