Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2
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ABSTRACT:
PROVIDER: PRJNA668354 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12802429_1.fastq.gz | Fastqsanger.gz | |||
| SRR12802429_2.fastq.gz | Fastqsanger.gz | |||
| SRR12802430_1.fastq.gz | Fastqsanger.gz | |||
| SRR12802430_2.fastq.gz | Fastqsanger.gz | |||
| SRR12802431_1.fastq.gz | Fastqsanger.gz |
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Project description:Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for hAT2 cells, and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and pro-inflammatory genes in infected hAT2 cells, indicating robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2, and the application of defined 3D hAT2 cultures as models for respiratory diseases.
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Project description:Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for hAT2 cells derived from primary human lung tissue, and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and pro-inflammatory genes in infected hAT2 cells, indicating robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2, and the application of defined 3D hAT2 cultures as models for respiratory diseases.
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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the cause of a present pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term, three-dimensional (3D) culture technique for hAT2 cells derived from primary human lung tissue and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and proinflammatory genes in infected hAT2 cells, indicating a robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2 and the application of defined 3D hAT2 cultures as models for respiratory diseases.
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Project description:SARS-CoV-2 seriously injures human alveoli and causes severe respiratory illness. Histopathologic evidences suggested alveolar-capillary barrier integrity is compromised in COVID-19 deaths, however, little is known about how it is disrupted. In this study, we investigated the effects of SARS-CoV-2 infection on alveolar epithelium and pulmonary microvascular endothelium, and tried to elucidate the cross-talk between them during viral infection. Under monoculture system, SARS-CoV-2 infection caused massive virus replication and dramatic organelles re-modeling in alveolar epithelial cells. While, as for pulmonary microvascular endothelial cells, direct viral exposure had little effect on them, but treatment with culture supernatant from infected epithelial cells significantly damaged them, which suggested SARS-CoV-2 affected endothelium indirectly, possibly by substances released from infected alveolar epithelium. Then, we tested SARS-CoV-2 infection in an alveolar epithelium/endothelium co-culture system, and found viral infection caused global proteomic modulations and ultrastructural changes in both cell types. Especially for alveolar epithelial cells, viral infection elicited significant protein changes and structural reorganizations across many sub-cellular compartments. Among the affected organelles, mitochondrion seems to be a primary target organelle. In addition, based on proteomic analysis and EM clues, we tested several autophagy inhibitors, and discovered one of them, Daurisoline, could inhibit virus replication effectively in cells. Collectively, our study revealed the distinctive responses of alveolar epithelium and microvascular endothelium to SARS-CoV-2 infection, which will expand our understanding of COVID-19 and helpful for targeted drug development.
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