A humanized mouse model of COVID-19
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ABSTRACT:
PROVIDER: PRJNA776028 | ENA |
REPOSITORIES: ENA
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Project description: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).
2021-11-04 | GSE186794 | GEO
Project description: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. MISTRG6 mouse model, engineered by a human/mouse homolog gene-replacement strategy, provides physiological factors for 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. 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. We evaluated the lung transcriptional landscape and response to therapeutics in this model. First, we assessed the impact of anti-IFNAR2 and Remdesivir combined therapy and control dexamethasone therapy on the immunological transcriptome of SARS-CoV-2 infected MISTRG6-hACE2 mice by focusing on differentially regulated human genes in whole lung tissue. We treated infected MISTRG6-hACE2 mice with Remdesivir, anti-IFNAR2 antibody or a combination of the two starting 7dpi, to sequentially target viral replication and the IFN-dependent cascade downstream of infection. As a control, we also treated mice with dexamethasone, one of the few treatments that significantly reduced hospitalization and mortality in the clinic. Next, we compared the single cell transcriptomes of human immune cells from infected mice late in disease (28dpi) with their uninfected counterparts to gain a deeper understanding of transcriptional changes at the cellular level. Finally, we focused our efforts on deeper characterization of monocyte/macrophage clusters at early (4dpi) or late (14 and 28dpi) infection.
2022-04-10 | GSE199272 | GEO
Project description: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. MISTRG6 mouse model, engineered by a human/mouse homolog gene-replacement strategy, provides physiological factors for 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. 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. We evaluated the lung transcriptional landscape and response to therapeutics in this model. First, we assessed the impact of anti-IFNAR2 and Remdesivir combined therapy and control dexamethasone therapy on the immunological transcriptome of SARS-CoV-2 infected MISTRG6-hACE2 mice by focusing on differentially regulated human genes in whole lung tissue. We treated infected MISTRG6-hACE2 mice with Remdesivir, anti-IFNAR2 antibody or a combination of the two starting 7dpi, to sequentially target viral replication and the IFN-dependent cascade downstream of infection. As a control, we also treated mice with dexamethasone, one of the few treatments that significantly reduced hospitalization and mortality in the clinic. Next, we compared the single cell transcriptomes of human immune cells from infected mice late in disease (28dpi) with their uninfected counterparts to gain a deeper understanding of transcriptional changes at the cellular level. Finally, we focused our efforts on deeper characterization of monocyte/macrophage clusters at early (4dpi) or late (14 and 28dpi) infection.
2022-04-10 | GSE200561 | GEO
Project description:Transcriptome Analaysis of humanized lungs in COVID-19
| PRJNA825270 | ENA
Project description:Aging is identified as a significant risk factor for severe coronavirus disease-2019 (COVID-19), often resulting in profound lung damage and mortality. Yet, the biological relationship between aging, aging-related comorbidities, and COVID-19 remains incompletely understood. This study aimed to elucidate the age-related COVID19 pathogenesis using a Hutchinson-Gilford progeria syndrome (HGPS) mouse model with humanized ACE2 receptors. Pathological features were compared between young, aged, and HGPS hACE2 mice following SAR-CoV-2 challenge. We demonstrated that young mice display robust interferon response and antiviral activity, whereas this response is attenuated in aged mice. Viral infection in aged mice results in severe respiratory tract bleeding, likely contributing a higher mortality rate. In contrast, HGPS hACE2 mice exhibit milder disease manifestations characterized by minor immune cell infiltration and dysregulation of multiple metabolic processes. Comprehensive transcriptome analysis revealed both shared and unique gene expression dynamics among different mouse groups. Collectively, our studies evaluated the impact of SARS-CoV-2 infection on progeroid syndromes using a HGPS hACE2 mouse model, which holds promise as a valuable tool for investigating COVID-19 pathogenesis in individuals with premature aging.
2024-08-28 | GSE264189 | GEO
Project description:Several humanized ACE2 (hACE2) mouse models have been developed for COVID-19 studies. Insertion of hACE2 at mouse Ace2 locus enables the utilization of endogenous promoter to drive its expression, better reflecting ACE2 abundance in various cell types and tissues. However, the relatively low expression of hACE2 in these mice may limit their fidelity in mimicking COVID-19 manifestations in humans and hinder their application in viral studies. In this study, we generated four hACE2 mouse models using different strategies for hACE2 expression. We found that the position of the β-globin intron within hACE2 cassette could have contrasting effects on hACE2 expression, with its placement downstream of hACE2 significantly increasing its transcription. Western blot analysis demonstrated that optimizing hACE2 codon usage further enhanced translation efficiency from all tested tissue. Consistent with elevated hACE2 expression, opt-hACE2 mice displayed more active immune response and severe COVID-19 phenotypes following SARS-CoV-2 challenging compared to other hACE2 mouse models. Thus, our study has elucidated the dual role of β-globin element in transgene expression, and highlighted that mice with optimized hACE2 codon preference could serve as a better model for SARS-CoV-2 studies.
2025-02-12 | GSE271163 | GEO
Project description:Definitive parameters or mechanisms underlying the severity of COVID-19 in elderly people remain confused. Thus, this study seeks to elucidate the mechanism behind the increased vulnerability of elderly individuals to severe COVID-19. We employed an aged mouse model with a mouse-adapted SARS-CoV-2 strain to mimic the severe symptoms observed in elderly patients with COVID-19. Comprehensive analyses of the whole lung were performed using transcriptome and proteome sequencing, comparing data from aged and young mice. For transcriptome analysis, bulk RNA sequencing was conducted using an Illumina sequencing platform.
2024-08-25 | GSE274784 | GEO
Project description:Transcriptome Analaysis of humanized lungs in COVID-19 [scRNAseq]
| PRJNA819093 | ENA
Project description:Transcriptome Analaysis of humanized lungs in COVID-19 [Bulk_RNAseq]
| PRJNA825272 | ENA
Project description:Acute cardiac injuries occur in 20%–25% of hospitalized COVID‐19 patients. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID‐19 hyperinflammation. As IL‐1β is an upstream cytokine and a core COVID‐19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID‐19 cytokine storm. The IL‐1β treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID‐19 hearts. The comparison of IL‐1β treated hCOs with cardiac tissue from COVID‐19 autopsies illustrated the critical roles of hyper‐inflammation in COVID‐19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL‐1β treated hCOs thus provide a defined and robust model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID‐19 cardiac in- juries at baseline and simulated exercise conditions.
2023-12-20 | GSE250520 | GEO