A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics
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ABSTRACT:
PROVIDER: PRJNA720637 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14183600.fastq.gz | Fastqsanger.gz | |||
| SRR14183601.fastq.gz | Fastqsanger.gz | |||
| SRR14183602.fastq.gz | Fastqsanger.gz | |||
| SRR14183603.fastq.gz | Fastqsanger.gz | |||
| SRR14183604.fastq.gz | Fastqsanger.gz |
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Project description:The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here, we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production, and the recruitment of circulating immune cells. In chips infected with pseudotyped SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection, but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential.
2021-04-09 | GSE171711 | GEO
Project description:The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production and the recruitment of circulating immune cells. In airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential.
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Project description:Identification of Candidate COVID-19 Therapeutics using hPSC-derived Lung Organoids
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Project description:The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex-vivo pediatric airway epithelial model (HAE) of hRSV infection. Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were specifically detected upon infection. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating (CXCL6, CXCL16, CSF3) and antiviral (CEACAM1) proteins never linked with this virus before. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium
2020-02-25 | PXD013661 | Pride
Project description:Rationale: Stem cell-based tracheal replacement represents an emerging therapeutic option for patients with otherwise untreatable airway diseases including long-segment congenital tracheal stenosis and upper airway tumors. Clinical experience suggests an urgent need to restore mucociliary function in the lungs following transplantation of tissue-engineered grafts, while pre-clinical studies show that seeding scaffolds with autologous mucosa improves regeneration. Recent data suggest that high epithelial cell seeding densities are required in regenerative medicine and existing techniques are inadequate to achieve coverage of clinically suitable grafts. Objectives: To define a scalable airway epithelial cell culture system to deliver airway epithelial cells to clinical grafts. Methods: Human respiratory epithelial cells derived from endobronchial biopsies were cultured using a combination of mitotically inactivated fibroblasts and Rho-kinase (ROCK) inhibition. Cells were analyzed using immunofluorescence, qPCR and flow cytometry to assess airway stem cell marker expression. Differentiation capacity and ciliary beat were assessed in air-liquid interface cultures. Karyotyping and an in vivo tracheal xenograft model were used to investigate the suitability of expanded cells for tracheal reconstruction. Measurements and Main Results: 3T3 feeder cells and ROCK inhibition allowed rapid expansion of airway basal stem cells. These cells were capable of multipotent airway differentiation in vitro, forming epithelia containing both ciliated and goblet lineages. Cilia were functional with normal beat frequency and pattern. Cultured cells repopulated a decellularized tracheal scaffold in a heterotopic tracheal transplantation xenograft model. Conclusions: Our method addresses the clinical need to generate large numbers of airway basal epithelial cells in the time window demanded by clinical transplantation.
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Project description:The innate immune protection provided by cationic antimicrobial peptides (CAMPs) has been shown to extend to antiviral activity, with putative mechanisms of action including direct interaction with host cells or pathogen membranes. The lack of therapeutics available for the treatment of viruses such as Venezuelan equine encephalitis virus (VEEV) underscores the urgency of novel strategies for antiviral discovery. American alligator plasma has been shown to exhibit strong in vitro antibacterial activity, and functionalized hydrogel particles have been successfully employed for the identification of specific CAMPs from alligator plasma. Here, a novel bait strategy in which particles were encapsulated in membranes from either healthy or VEEV-infected cells was implemented to identify peptides preferentially targeting infected cells for subsequent evaluation of antiviral activity. Statistical analysis of peptide identification results was used to select five candidate peptides for testing, of which three exhibited a dose-dependent inhibition of VEEV, with one peptide also significantly inhibiting infectious titers. Results suggest our bioprospecting strategy provides a versatile platform that may be adapted for antiviral peptide identification from complex biological samples.
2022-05-27 | MSV000089560 | MassIVE
Project description:Exosomes are extracellular vesicles secreted by cells that have an important biological function in intercellular communication by transferring biologically active proteins, lipids, and RNAs to neighbouring or distant cells. While a role for exosomes in antimicrobial defence has recently emerged, currently very little is known regarding the nature and functional relevance of exosomes generated in vivo, particularly during an active viral infection. Here, we characterised exosomes released into the airways during influenza virus infection. We show that these vesicles dynamically change in protein composition over the course of infection, increasing expression of host proteins with known anti-influenza activity, and viral proteins with the potential to trigger host immune responses. We show that exosomes released into the airways during influenza virus infection trigger pulmonary inflammation and carry viral antigen that can be utilized by antigen presenting cells to drive the induction of a cellular immune response. Moreover, we show that attachment factors for influenza virus, namely α2,3 and α2,6-linked sialic acids, are present on the surface of airway exosomes and these vesicles have the ability to neutralize influenza virus, thereby preventing the virus from binding and entering target cells. These data reveal a novel role for airway exosomes in the antiviral innate immune defence against influenza virus infection.
2020-06-03 | PXD018389 | Pride
Project description:Introduction: Thymic Stromal Lymphopoietin (TSLP) is a primarily epithelial-derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. Methods: A total of 129 infants (<1m – 24m, median age 10m) with severe viral respiratory infections were enrolled for in vivo (n=113), and in vitro studies (n=16). Infants were classified as “high TSLP” or “low TSLP” for values above or below the 50th percentile. High vs. low TSLP groups were compared in terms of type I-III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high vs. low TSLP responses in vitro. Results: Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/ml vs. 63.4 pg/ml in low TSLP group, p= 0.007) and increased in vitro type I-III IFN AEC responses after stimulation with a viral mimic (poly I:C). Our RNAseq data showed that infants in the high TSLP group had significant baseline upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro-inflammatory chemokine genes prior to viral mimic stimulation. Infants in the high TSLP group also showed a baseline AEC pro-inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8) in the absence of viral stimuli. Conclusion: High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro-inflammatory chemokines. These findings present a new paradigm underlying the high production of TSLP in the human infant airway epithelium and shed light on the pathogenesis of viral respiratory illnesses during early infancy and beyond childhood.
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