A bipotential organoid culture of respiratory epithelium for modeling SARS-CoV-2 infection
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ABSTRACT:
PROVIDER: PRJNA783307 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17029924_1.fastq.gz | Fastqsanger.gz | |||
| SRR17029924_2.fastq.gz | Fastqsanger.gz | |||
| SRR17029925_1.fastq.gz | Fastqsanger.gz | |||
| SRR17029925_2.fastq.gz | Fastqsanger.gz | |||
| SRR17029926_1.fastq.gz | Fastqsanger.gz |
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Project description:The airways and the alveoli of the human respiratory tract are lined by two distinct types of epithelium. We previously established long-term expanding human lung epithelial organoids from lung tissues and developed a ‘proximal’ differentiation protocol to generate mucociliary airway organoids, yet the derivation of alveolar organoids from adult lung has remained a challenge. Here we defined a ‘distal’ differentiation approach to generate alveolar organoids from the same source that allows the establishment of airway organoids. Alveolar organoids are enriched for AT1 and AT2 cells and functionally simulate the alveolar epithelium. AT2 cells in lung organoids act as the progenitor cells from which alveolar organoids emerge. Moreover, we demonstrate productive SARS-CoV-2 infection of alveolar organoids. We further optimize 2-dimensional (2D) airway organoids. When differentiated under a slightly acidic pH, these 2D airway organoids sustain enhanced viral replication and better recapitulate the high infectivity of SARS-CoV-2. Moreover, the optimized 2D airway organoids can model IgG transcytosis across the airway epithelium. Collectively, we establish a bipotential organoid culture system that can reproducibly expand the entire human respiratory epithelium in vitro for modeling respiratory diseases, including COVID-19.
2022-06-22 | GSE189514 | GEO
Project description:The airways and alveoli of the human respiratory tract are lined by two distinct types of epithelium, which are the primary targets of respiratory viruses. We previously established long-term expanding human lung epithelial organoids from lung tissues and developed a 'proximal' differentiation protocol to generate mucociliary airway organoids. However, a respiratory organoid system with bipotential of the airway and alveolar differentiation remains elusive. Here we defined a 'distal' differentiation approach to generate alveolar organoids from the same source for the derivation of airway organoids. The alveolar organoids consisting of type I and type II alveolar epithelial cells (AT1 and AT2, respectively) functionally simulate the alveolar epithelium. AT2 cells maintained in lung organoids serve as progenitor cells from which alveolar organoids derive. Moreover, alveolar organoids sustain a productive SARS-CoV-2 infection, albeit a lower replicative fitness was observed compared to that in airway organoids. We further optimized 2-dimensional (2D) airway organoids. Upon differentiation under a slightly acidic pH, the 2D airway organoids exhibit enhanced viral replication, representing an optimal in vitro correlate of respiratory epithelium for modeling the high infectivity of SARS-CoV-2. Notably, the higher infectivity and replicative fitness of the Omicron variant than an ancestral strain were accurately recapitulated in these optimized airway organoids. In conclusion, we have established a bipotential organoid culture system able to reproducibly expand the entire human respiratory epithelium in vitro for modeling respiratory diseases, including COVID-19.
| S-EPMC9203776 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic resulting from zoonotic transmission of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Severe symptoms include viral pneumonia secondary to infection and inflammation of the lower respiratory tract, in some cases causing death. We developed primary human lung epithelial infection models to understand responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface cultures of proximal airway epithelium and 3D organoid cultures of alveolar epithelium were readily infected by SARS-CoV-2 leading to an epithelial cell-autonomous proinflammatory response. We validated the efficacy of selected candidate COVID-19 drugs confirming that Remdesivir strongly suppressed viral infection/replication. We provide a relevant platform for studying COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and future emergent respiratory pathogens.
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Project description:Organoid modeling of the tumor immune microenvironment
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Project description:The interaction of neoplastic cells with their tumor microenvironment (TME) is required for cancer progression. However, in vitro cancer models, including recent in vitro 3-dimensional (3D) organoid cultures of primary human tumors, are typically comprised exclusively of neoplastic epithelium, with stromal and/or immune interactions requiring artificial reconstitution. As relevant to cancer immunotherapy, the unified co-culture of primary tumor epithelia with their endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has remained particularly elusive. Here, we used a single 3D air-liquid interface (ALI) methodology to successfully propagate 3D Patient-Derived Tumor Organoids (PDOs) as primary tumor epithelia together with native immune and myofibroblast stromal compartments without reconstitution. Derived from >100 diverse human surgically resected tumor samples or from murine tumors in syngeneic immunocompetent mice, PDOs preserved cancer histologic subtypes and mutational spectrum with endogenous T, B, NK cells and macrophages integrally embedded amidst the tumor epithelium. PDO-based TILs accurately recapitulated the T cell receptor (TCR) spectrum of the original tumors, as determined by a robust droplet-based immune profiling solution that links gene expression and immune repertoire in single cells. Anti-PD-1 or anti-PD-L1 treatment of organoids from murine tumors from syngeneic immunocompetent hosts induced activation and cytolytic activity of tumor antigen-specific TILs, indicating successful PDO modeling of immune checkpoint blockade (ICB) and anti-tumor immunity. Crucially, the anti-PD-1 antibody nivolumab activated TILs in PDOs from human lung, renal and melanoma clinical tumor resections. The organoid-based propagation of primary tumor epithelium en bloc with its endogenous immune stroma should facilitate mechanistic investigation of TME-specific local tumor immunity, with applications for functional testing of individualized patient immunotherapy responses.
2018-12-13 | GSE111360 | GEO
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2020-07-24 | E-MTAB-9339 | biostudies-arrayexpress
Project description:Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic resulting from zoonotic transmission of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Severe symptoms include viral pneumonia secondary to infection and inflammation of the lower respiratory tract, in some cases causing death. We developed primary human lung epithelial 5 infection models to understand responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface cultures of proximal airway epithelium and 3D organoid cultures of alveolar epithelium were readily infected by SARS-CoV-2 leading to an epithelial cell-autonomous proinflammatory response. We validated the efficacy of selected candidate COVID-19 drugs confirming that Remdesivir strongly suppressed viral 10 infection/replication. We provide a relevant platform for studying COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and future emergent respiratory pathogens.
2020-11-06 | GSE160435 | GEO
Project description:Background: In asthma, airway epithelium remodeling can already be detected during childhood, and epithelial cells are more susceptible to virus and oxidative stress. Their exact role in natural history and severity of children allergic respiratory disease remains however surprisingly unexplored. Aim: To analyze dysfunctions of epithelium in dust mite allergic respiratory disease (rhinitis ± asthma) in children. Methods: Expression profilings of nasal epithelial cells collected by brushing were performed on Affymetrix Hugene 1.0 ST arrays. All allergic patients were sensitized to dust mite. 19 patients had an isolated allergic rhinitis (AR). 14 patients had AR associated with asthma. Patients were compared to 12 controls, their severity and control being assessed according to NAEPP and ARIA criteria. Infections by respiratory viruses were excluded by real-time PCR measurements. Results: 61 probes were able to distinguish allergic rhinitis children from healthy controls. A majority of these probes was under the control of Th2 cytokines, as evidenced by parallel experiments performed on primary cultures of nasal epithelial cells. In uncontrolled asthmatic patients, we observed not only an enhanced expression of these Th2-responsive transcripts, but also a down-regulation of interferon-responsive genes. Conclusion: Our study identifies a Th2 driven epithelial phenotype common to all dust mite allergic children. Besides, it suggests that epithelium is involved in the severity of the disease. Expression profiles observed in uncontrolled asthmatic patients suggest that severity of asthma is linked at the same time to atopy and to impaired viral response. Nasal epithelium gene expression profiling of dust mite allergic children with isolated rhinitis, rhinitis associated with asthma and controls. 38 samples classified in 4 categories : 14 isolated rhinitis (R), 6 rhinitis with uncontrolled asthma (UA), 7 rhinitis with controlled asthma (CA) and 11 healthy subjects (C )
2012-01-05 | E-GEOD-19187 | biostudies-arrayexpress
Project description:Background: In asthma, airway epithelium remodeling can already be detected during childhood, and epithelial cells are more susceptible to virus and oxidative stress. Their exact role in natural history and severity of children allergic respiratory disease remains however surprisingly unexplored. Aim: To analyze dysfunctions of epithelium in dust mite allergic respiratory disease (rhinitis ± asthma) in children. Methods: Expression profilings of nasal epithelial cells collected by brushing were performed on Affymetrix Hugene 1.0 ST arrays. All allergic patients were sensitized to dust mite. 19 patients had an isolated allergic rhinitis (AR). 14 patients had AR associated with asthma. Patients were compared to 12 controls, their severity and control being assessed according to NAEPP and ARIA criteria. Infections by respiratory viruses were excluded by real-time PCR measurements. Results: 61 probes were able to distinguish allergic rhinitis children from healthy controls. A majority of these probes was under the control of Th2 cytokines, as evidenced by parallel experiments performed on primary cultures of nasal epithelial cells. In uncontrolled asthmatic patients, we observed not only an enhanced expression of these Th2-responsive transcripts, but also a down-regulation of interferon-responsive genes. Conclusion: Our study identifies a Th2 driven epithelial phenotype common to all dust mite allergic children. Besides, it suggests that epithelium is involved in the severity of the disease. Expression profiles observed in uncontrolled asthmatic patients suggest that severity of asthma is linked at the same time to atopy and to impaired viral response. Nasal epithelium gene expression profiling of dust mite allergic children with isolated rhinitis, rhinitis associated with asthma and controls.
2012-01-05 | GSE19187 | GEO