SRP343662 PRJNA776028 GSE186794 A humanized mouse model of COVID-19 Mice with a human immune system (humanized mice), generated by transplantation of human hematopoietic stem and progenitor cells (HSPCs), serve as invaluable tools to study the development and function of the human immune system in vivo. By adapting recombinant adeno-associated virus (AAV)-driven gene therapy to deliver hACE2 to the lungs, which allows infection with SARS-CoV-2 of MISTRG6 mice engrafted with HPSCs, we created a humanized mouse model of COVID-19 that recapitulates the distribution and function of the human innate and adaptive immune system and is amenable to the mechanistic study of COVID-19 and its myriad of complications. MISTRG6 mouse model was engineered by a human/mouse homolog gene-replacement strategy to provide physiological factors with regard to quantity, location and time and enable essentially all classes of human HSPCs to develop in mice. MISTRG6 (acronym for genes replaced) mice encode humanized M-CSF (enabling monocytes and tissue macrophage development), GM-CSF/IL-3 (to provide lung alveolar macrophages), SIRPa (establish macrophage tolerance to human cells), ThPO (hematopoiesis and platelets), and IL-6 (better engraftment allowing study of adult human patients and improved antigen-specific antibody responses as well as human IL-6 per se), in a Rag2/Gamma common chain deleted background. We evaluated the transcriptional landscape in uninfected and SARS-CoV-2 infected lungs of humanized mice at multiple time points (2, 4, 7, 14, 28 dpi). Overall design: We delivered AAV-hACE2 to lung tissues of immune-reconstituted MISTRG6 mice (MISTRG6-hACE2) that have been engrafted with human HSPCs. MISTRG6-hACE2 mice were then infected with SARS-CoV-2. Lung tissues from infected and uninfected controls were collected. RNA isolated from homogenized lung tissue was used for whole tissue transcriptome analysis. Libraries were prepared with an Illumina rRNA depletion kit and sequenced on a NovaSeq. GSE186794 pubmed 35483404