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Transcriptome Analaysis of humanized lungs in COVID-19 [Bulk_RNAseq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE200561 | GEO | 2022/04/10

REPOSITORIES: GEO

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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. 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.

Project description:Rapid emergence of antigenic distinct SARS-CoV-2 variants implies a greater risk of reinfection as viruses can escape neutralizing antibodies induced by vaccination or previous viral exposure. Disease severity during COVID-19 depends on many variables such as age-related comorbidities, host immune status and genetic variation. The host immune response during infection with SARS-CoV-2 may contribute to disease severity, which can range from asymptomatic to severe with fatal outcome. Furthermore, the extent of host immune response activation may rely on underlying genetic predisposition for disease or protection. To address these questions, we performed immune profiling studies in mice with different genetic backgrounds - transgenic K18-hACE2 and wild-type 129S1 mice – subjected to reinfection with the severe disease-causing SARS-CoV-2 B.1.351 variant, 30 days after experimental milder BA.1 infection. BA.1 preinfection conferred protection against B.1.351-induced morbidity in K18-hACE2 mice but aggravated disease in 129S1 mice. We found that he cytokine/chemokine profile in B.1.351 re-infected 129S1mice is similar to that during severe SARS-CoV-2 infection in humans and is characterized by a much higher level of IL-10, IL-1β, IL-18 and IFN-γ , whereas in B.1.351 re-infected K18-hACE2 mice, the cytokine profile echoes the signature of naïve mice undergoing viral infection for the first time. Interestingly, the enhanced pathology observed in 129S1 mice upon reinfection cannot be attributed to a less efficient induction of adaptive immune responses to the initial BA.1 infection, as both K18-hACE2 and 129S1 mice exhibited similar B and T cell responses at 30 DPI against BA.1, with similar anti-BA.1 or B.1.351 spike-specific ELISA binding titers, levels of germinal center B-cells, and SARS-CoV-2-Spike specific tissue-resident T-cells. Long-term effects of BA.1 infection are associated with differential transcriptional changes in bronchoalveolar lavage-derived CD11c+ immune cells from K18-hACE2 and 129S1, with K18-hACE2 CD11c+ cells showing a strong antiviral defense gene expression profile whereas 129S1 CD11c+ cells showed a more pro-inflammatory response. In conclusion, initial infection with BA.1 induces cross-reactive adaptive immune responses in both K18-hACE2 and 129S1 mice, however the different disease outcome of reinfection seems to be driven by differential responses of CD11c+ cells in the alveolar space.

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Transcriptome Analaysis of humanized lungs in COVID-19 [Bulk_RNAseq]

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