Similar Datasets
Project description:Although the impact of SARS-CoV-2 in the lung has been extensively studied, the molecular regulators and targets of the host-cell programs hijacked by the virus in distinct human airway epithelial cell populations remain poorly understood. This is in part ascribed to the use of non-primary cell systems, overreliance on single-cell gene expression profiling that not ultimately reflect protein activity and bias toward the downstream effects rather than their mechanistic determinants. Here we address these issues by network-based analysis of single cell transcriptomic profiles of pathophysiologically relevant human adult basal, ciliated and secretory cells to identify master regulator (MR) protein modules controlling their SARS-CoV-2-mediated reprogramming. This uncovered chromatin remodeling, endosomal sorting, ubiquitin pathway as well as proviral factors identified by CRISPR analyses as components of the host response collectively or selectively activated in these cells. Large-scale perturbation assays, using a clinically-relevant drug library, identified 11 drugs able to invert the entire MR signature activated by SARS-CoV-2 in these cell types. Leveraging MR analysis and perturbational profiles of human primary cells, represents a novel mechanism-based approach and resource that can be directly generalized to interrogate signatures of other airway conditions for drug prioritization.
| S-EPMC11507692 | biostudies-literature
Project description:The conducting airway epithelium is the first line of defense in the respiratory tract against pathogens and a prime site of SARS-CoV-2 viral entry, serving to maintain a high viral load during lung infection. The impact of SARS-CoV-2 infection in the respiratory epithelium has been extensively studied. However, still less is known about the regulators of SARS-Cov-2-induced programs that facilitate infection and viral replication in distinct human airway epithelial cell populations, such as basal, secretory, and multiciliated cells. Here, we used SARS-CoV-2-infection of human airway epithelial organotypic cultures, single cell transcriptomics, large FDA-approved drug perturbation profiles combined with Master Regulator analysis to identify host cell defense and response pathways determinants of viral infection
2025-05-18 | GSE262299 | GEO
Project description:The conducting airway epithelium is the first line of defense in the respiratory tract against pathogens and a prime site of SARS-CoV-2 viral entry, serving to maintain a high viral load during lung infection. The impact of SARS-CoV-2 infection in the respiratory epithelium has been extensively studied. However, still less is known about the regulators of SARS-Cov-2-induced programs that facilitate infection and viral replication in distinct human airway epithelial cell populations, such as basal, secretory, and multiciliated cells. Here, we used SARS-CoV-2-infection of human airway epithelial organotypic cultures, single cell transcriptomics, large FDA-approved drug perturbation profiles combined with Master Regulator analysis to identify host cell defense and response pathways determinants of viral infection
2025-05-18 | GSE262298 | GEO
Project description:Identification and Targeting of Regulators of SARS-CoV-2-Host interactions in the Airway Epithelium
| PRJNA1092598 | ENA
Project description:Identification and Targeting of Regulators of SARS-CoV-2-Host interactions in the Airway Epithelium [PlateSeq]
| PRJNA1091175 | ENA
Project description:Identification and Targeting of Regulators of SARS-CoV-2-Host interactions in the Airway Epithelium [scRNA-Seq]
| PRJNA1091174 | ENA
Project description:Despite the availability of vaccines and therapeutics, continual genetic alterations render the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) a persistent threat, particularly for the immunocompromised and elderly. Through interactions of its spike (S) protein with different receptors and coreceptors on host cell surfaces, the virus enters the cell either via fusion with the plasma membrane or through endocytosis. Angiotensin-converting enzyme 2 (ACE2) has been identified as a key receptor utilized by SARS-CoV-2 and related human coronaviruses to mediate cell entry in the lung airways. Auxiliary SARS-CoV-2 entry receptors such as ASGPR1, Kremen protein 1, integrins have also been reported. In this review, therapeutic approaches to block SARS-CoV-2 and host cell receptor interactions are discussed.
| S-EPMC9792186 | biostudies-literature
Project description:Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Here, we examined human airway epithelium infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistently, extracellular virions were seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion where tomography showed that the viral membrane was continuous with the apical plasma membrane and the nucleocapsids diluted, compared with unfused virus, demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Tomography showed concentration of nucleocapsids round the periphery of profiles strongly suggestive of viral budding into these compartments and this may explain how virions gain their S glycoprotein containing envelope.
| S-EPMC8956608 | biostudies-literature
Project description:SARS-CoV-2, the causative agent of COVID-19, has tragically burdened individuals and institutions around the world. There are currently no approved drugs or vaccines for the treatment or prevention of COVID-19. Enhanced understanding of SARS-CoV-2 infection and pathogenesis is critical for the development of therapeutics. To reveal insight into viral replication, cell tropism, and host-viral interactions of SARS-CoV-2 we performed single-cell RNA sequencing of experimentally infected human bronchial epithelial cells (HBECs) in air-liquid interface cultures over a time-course. This revealed novel polyadenylated viral transcripts and highlighted ciliated cells as a major target of infection, which we confirmed by electron microscopy. Over the course of infection, cell tropism of SARS-CoV-2 expands to other epithelial cell types including basal and club cells. Infection induces cell-intrinsic expression of type I and type III IFNs and IL6 but not IL1. This results in expression of interferon-stimulated genes in both infected and bystander cells. We observe similar gene expression changes from a COVID-19 patient ex vivo. In addition, we developed a new computational method termed CONditional DENSity Embedding (CONDENSE) to characterize and compare temporal gene dynamics in response to infection, which revealed genes relating to endothelin, angio-genesis, interferon, and inflammation-causing signaling pathways. In this study, we conducted an in-depth analysis of SARS-CoV-2 infection in HBECs and a COVID-19 patient and revealed genes, cell types, and cell state changes associated with infection.
| S-EPMC7263511 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause the ongoing pandemic of coronavirus disease 2019 (COVID19). One key feature associated with COVID-19 is excessive pro-inflammatory cytokine production that leads to severe acute respiratory distress syndrome. Although the cytokine storm induces inflammatory cell death in the host, which type of programmed cell death mechanism that occurs in various organs and cells remains elusive. Using an in vitro culture model of polarized human airway epithelium (HAE), we observed that necroptosis, but not apoptosis or pyroptosis, plays an essential role in the damage of the epithelial barrier of polarized HAE infected with SARS-CoV-2. Pharmacological inhibitors of necroptosis, necrostatin-2 and necrosulfonamide, efficiently prevented cell death and epithelial barrier dysfunction caused by SARS-CoV-2 infection. Moreover, the silencing of genes that are involved in necroptosis, RIPK1, RIPK3, and MLKL, ameliorated airway epithelial damage of the polarized HAE infected with SARS-CoV-2. This study, for the first time, confirms that SARS-CoV-2 infection triggers necroptosis that disrupts the barrier function of human airway epithelia in vitro.
| S-EPMC10754389 | biostudies-literature