Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium
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ABSTRACT:
PROVIDER: PRJNA661567 | ENA |
REPOSITORIES: ENA
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Project description:The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNAseq to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of cell types are susceptible to infection, ciliated cells are a predominant cell target for SARS-CoV-2. Remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. We also found that heavily infected epithelial cells demonstrate impaired IFN signaling and express abundant IL-6, a potential mediator of COVID-19 pathogenesis.
2020-11-02 | GSE157526 | GEO
Project description:The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.
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Project description:The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.
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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:Enteroviruses (EVs) are one of the most prevalent viruses worldwide. They are characterised by a high genetic and phenotypic diversity, being able to cause a plethora of symptoms. EV-D68, a respiratory EV, and EV-D94, an enteric EV, represent an interesting paradigm of EV tropism heterogeneity. These are closely related viruses, belonging to the same species, but with distinct phenotypic features. Here, we used these two viruses as well as relevant tissue culture models mimicking the respiratory and intestinal epithelia, to highlight key distinctive features of enteric and respiratory EVs. We emphasize the critical role of temperature in restricting the tissue tropism of EV-D68 and the limited replication of EV-D94 in small airway tissues. In parallel, using transcriptomic analysis, we uncover fundamental differences between intestinal and respiratory tissues, in their steady-state as well as in response to infection. Intestinal tissues are more immunotolerant than respiratory tissues both in absence and presence of infection and they present higher turnover. Finally, we highlight the different strategies applied by EV-D94 and EV-D68 towards the host antiviral response in intestinal and respiratory tissues. In summary, our study provides an insightful characterization of the differential pathogenesis of EV-D68 and EV-D94 and the interplay with their main target tissues.
2022-06-23 | GSE184488 | GEO
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Project description:Rationale: Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non-small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown.Objectives: To comprehensively survey the somatic mutational architecture of the normal airway epithelium in patients with early-stage NSCLC.Methods: Multiregion normal airways, comprising tumor-adjacent small airways, tumor-distant large airways, nasal epithelium and uninvolved normal lung (collectively airway field), matched NSCLCs, and blood cells (n = 498) from 48 patients were interrogated for somatic single-nucleotide variants by deep-targeted DNA sequencing and for chromosomal allelic imbalance events by genome-wide genotype array profiling. Spatiotemporal relationships between the airway field and NSCLCs were assessed by phylogenetic analysis.Measurements and Main Results: Genomic airway field carcinogenesis was observed in 25 cases (52%). The airway field epithelium exhibited a total of 269 somatic mutations in most patients (n = 36) including key drivers that were shared with the NSCLCs. Allele frequencies of these acquired variants were overall higher in NSCLCs. Integrative analysis of single-nucleotide variants and allelic imbalance events revealed driver genes with shared "two-hit" alterations in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits progressing to two in the NSCLCs (e.g., PIK3CA and NOTCH1).Conclusions: Tumor-adjacent and tumor-distant normal-appearing airway epithelia exhibit somatic driver alterations that undergo selection-driven clonal expansion in NSCLC. These events offer spatiotemporal insights into the development of NSCLC and, thus, potential targets for early treatment.
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Project description:We report that the cell of origin plays an important role in this metastatic tropism. Following injection into the arterial circulation of mice, each of the identically transformed cell types gave rise to different metastatic patterns. Using gene expression analysis, we identified the chemokine receptor CXCR4 as being instrumental in determining the distinct metastatic patterns between skeletal muscle precursor cells and skeletal myoblasts. 3 independent cell lines of primary human skeletal myoblasts, primary skeletal muscle cell precursors, and each of these cell lines transformed with hTERT, the early region of SV40 encoding T-Ag and t-Ag, and RasG12V analysis of primary human skeletal myoblasts, primary skeletal muscle cell precursors, and each of these cell lines transformed with hTERT, the early region of SV40 encoding T-Ag and t-Ag, and RasG12V
2016-02-13 | E-GEOD-19294 | biostudies-arrayexpress
Project description:Extrapulmonary manifestations of COVID-19 have gained attention, not only due to their links to clinical outcomes, but also due to their potential long-term sequelae1. Recent evidence has shown multi-organ tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including heart, kidney and liver2. Previous studies have shown that close to 20% of hospitalized patients with COVID-19 develop liver injury, showing an association to disease severity3. Here, we identified a high frequency of liver enzyme alterations at admission in COVID-19 patients who required hospitalization. Then, we characterized SARS-CoV-2 liver tropism in autopsy samples, based on the expression of cell-entry facilitators in parenchymal cells, clinical polymerase chain reaction (PCR) positivity, subgenomic SARS-CoV-2 identification using RNA sequencing, and viral RNA detection by in situ hybridization. Next, we unraveled the transcriptomic and proteomic landscape of SARS-CoV-2 liver tropism, revealing significant increases in interferon alpha and gamma signaling and compensatory liver-specific metabolic regulation. While these results reflect changes in tissues from patients with severe SARS-CoV-2 infection, these profound molecular alterations raise questions about the potential long-term consequences of COVID-19 infection.
2022-04-02 | PXD022789 | Pride
Project description:Genomic Factors Related to Tissue Tropism in Chlamydia pneumoniae Infection
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