Human Nasal Epithelial Cells sustain persistent SARS-CoV-2 infection in vitro, despite eliciting a prolonged antiviral response.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE182475 | GEO | 2022/01/04
REPOSITORIES: GEO
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Project description:The dynamics of SARS-CoV-2 infection in COVID-19 patients are highly variable, with a subset of patients demonstrating prolonged virus shedding, which poses a significant challenge for disease management and transmission control. In this study, the long-term dynamics of SARS-CoV-2 infection were investigated using a human well-differentiated nasal epithelial cell (NEC) model of infection. NECs were observed to release SARS-CoV-2 virus onto the apical surface for up to 28 days postinfection (dpi), further corroborated by viral antigen staining. Single-cell transcriptome sequencing (sc-seq) was utilized to explore the host response from infected NECs after short-term (3-dpi) and long-term (28-dpi) infection. We identified a unique population of cells harboring high viral loads present at both 3 and 28 dpi, characterized by expression of cell stress-related genes DDIT3 and ATF3 and enriched for genes involved in tumor necrosis factor alpha (TNF-α) signaling and apoptosis. Remarkably, this sc-seq analysis revealed an antiviral gene signature within all NEC cell types even at 28 dpi. We demonstrate increased replication of basal cells, absence of widespread cell death within the epithelial monolayer, and the ability of SARS-CoV-2 to replicate despite a continuous interferon response as factors likely contributing to SARS-CoV-2 persistence. This study provides a model system for development of therapeutics aimed at improving viral clearance in immunocompromised patients and implies a crucial role for immune cells in mediating viral clearance from infected epithelia. IMPORTANCE Increasing medical attention has been drawn to the persistence of symptoms (long-COVID syndrome) or live virus shedding from subsets of COVID-19 patients weeks to months after the initial onset of symptoms. In vitro approaches to model viral or symptom persistence are needed to fully dissect the complex and likely varied mechanisms underlying these clinical observations. We show that in vitro differentiated human NECs are persistently infected with SARS-CoV-2 for up to 28 dpi. This viral replication occurred despite the presence of an antiviral gene signature across all NEC cell types even at 28 dpi. This indicates that epithelial cell intrinsic antiviral responses are insufficient for the clearance of SARS-CoV-2, implying an essential role for tissue-resident and infiltrating immune cells for eventual viral clearance from infected airway tissue in COVID-19 patients.
| S-EPMC8764519 | biostudies-literature
Project description:Human Nasal Epithelial Cells sustain persistent SARS-CoV-2 infection in vitro, despite eliciting a prolonged antiviral response.
| PRJNA756316 | ENA
Project description:The nasal epithelium is the primary initial site of SARS-CoV-2 entry in the human body. Since much of the molecular detail defining coronavirus entry and replication was derived from non-nasal cell lines, it remains unclear how SARS-CoV-2 overcomes the physical nasal mucus and periciliary mucin layers to infect and spread through the nasal epithelium. Using air-liquid interface cultured primary nasal epithelial cells, we observed that SARS-CoV-2 attaches to motile cilia during the initial stage of infection. Depletion of cilia inhibited SARS-CoV-2, as well as respiratory syncytial virus and parainfluenza virus infection, suggesting a widely-used ciliary mechanism for respiratory viral entry. Using electron and immunofluorescence microscopy, we further observed that SARS-CoV-2 progeny virions attached to airway microvilli 24 hours post infection and triggered the formation of apically extended and highly branched microvilli that organize viral egress from the microvillar base back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Chemical perturbation of microvillus formation severely impaired viral egress and subsequent spread. Phosphoproteomic analyses indicate that virally-triggered microvillar branching is linked to the p21-activated kinase 1 and 4 (PAK1/4) signaling pathway and viral infection is impaired by PAK1/4 kinase inhibitors. Our work provides insight into the mechanisms by which SARS-CoV-2 and potentially many respiratory viruses penetrate the physical nasal epithelium barrier, a first line of defense against pathogens, thus revealing a new view of the motile cilia and microvilli as critical host factors required for viral entry and egress.
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Project description:Detection of SARS-CoV-2 using RT–PCR and other advanced methods can achieve high accuracy. However, their application is limited in countries that lack sufficient resources to handle large-scale testing during the COVID-19 pandemic. Here, we describe a method to detect SARS-CoV-2 in nasal swabs using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and machine learning analysis. This approach uses equipment and expertise commonly found in clinical laboratories in developing countries. We obtained mass spectra from a total of 362 samples (211 SARS-CoV-2-positive and 151 negative by RT–PCR) without prior sample preparation from three different laboratories. We tested two feature selection methods and six machine learning approaches to identify the top performing analysis approaches and determine the accuracy of SARS-CoV-2 detection. The support vector machine model provided the highest accuracy (93.9%), with 7% false positives and 5% false negatives. Our results suggest that MALDI-MS and machine learning analysis can be used to reliably detect SARS-CoV-2 in nasal swab samples.
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Project description:Considering the complex and multifarious features of Chronic rhinosinusitis (CRS) including immunologic patterns, novel modalities are needed to reflect clinical and pathophysiological endotypes beyond nasal polyps.We aimed to investigate the proteome of nasal secretions on filter paper from CRS patients to characterize endotypes.
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| S-EPMC6712565 | biostudies-literature