ArticleJournal of advanced research2024
Modifications of lipid pathways restrict SARS-CoV-2 propagation in human induced pluripotent stem cell-derived 3D airway organoids.
Article in Journal of advanced research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 10 citations in OpenAlex.
- Applications of human lung organoids to human respiratory virus research: advances, limitations and future directions.Infection · 2025Review
- Membrane-Targeting Antivirals.International journal of molecular sciences · 2025Review
- Direct pharmacological AMPK activation inhibits mucosal SARS-CoV-2 infection by reducing lipid metabolism, restoring autophagy flux and the type I IFN response.Journal of virology · 2025Article
- Epitranscriptomic Modulation of TET2 Inhibition Suppressed SARS-CoV-2 Infection and Blocked Viral Nucleocapsid Protein in Induced-Pluripotent-Stem-Cell-Derived Cardiomyocyte Screening Models.Biomaterials research · 2025Article
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Authors and funding
21 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundModifications of lipid metabolism were closely associated with the manifestations and prognosis of coronavirus disease of 2019 (COVID-19). Pre-existing metabolic conditions exacerbated the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while modulations of aberrant lipid metabolisms alleviated the manifestations. To elucidate the underlying mechanisms, an experimental platform that reproduces human respiratory physiology is required.
methodsHere we generated induced pluripotent stem cell-derived airway organoids (iPSC-AOs) that resemble the human native airway. Single-cell sequencing (ScRNAseq) and microscopic examination verified the cellular heterogeneity and microstructures of iPSC-AOs, respectively. We subjected iPSC-AOs to SARS-CoV-2 infection and investigated the treatment effect of lipid modifiers statin drugs on viral pathogenesis, gene expression, and the intracellular trafficking of the SARS-CoV-2 entry receptor angiotensin-converting enzyme-2 (ACE-2).
resultsIn SARS-CoV-2-infected iPSC-AOs, immunofluorescence staining detected the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins and bioinformatics analysis further showed the aberrant enrichment of lipid-associated pathways. In addition, SARS-CoV-2 hijacked the host RNA replication machinery and generated the new isoforms of a high-density lipoprotein constituent apolipoprotein A1 (APOA1) and the virus-scavenging protein deleted in malignant brain tumors 1 (DMBT1). Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2) and decreased N protein expression, leading to the reduction of SARS-CoV-2 entry and replication. The same lipid modifications suppressed the entry of luciferase-expressing SARS-CoV-2 pseudoviruses containing the S proteins derived from different SARS-CoV-2 variants, i.e. wild-type, alpha, delta, and omicron.
conclusionsTogether, our data demonstrated that modifications of lipid pathways restrict SARS-CoV-2 propagation in the iPSC-AOs, which the inhibition is speculated through the translocation of ACE2 from the cell membrane to the cytosol. Considering the highly frequent mutation and generation of SARS-CoV-2 variants, targeting host metabolisms of cholesterol or other lipids may represent an alternative approach against SARS-CoV-2 infection.
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