ArticleThe Journal of clinical investigation2022
Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 44 citations in OpenAlex.
- IFITM1 and IFITM3 cooperate to restrict virus entry in endolysosomes.Journal of virology · 2026Article
- Drug Repurposing as a Broad-Spectrum Strategy Against Coronaviruses: Frontiers in Mechanisms and Clinical Translation.Viruses · 2026Review
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- NRF2 controls a diverse network of antiviral effectors with p62 acting as a central restriction factor effective across virus families.Redox biology · 2026Article
- Machine learning, whole genome sequencing, and Mendelian randomization support a role of CRP on COVID-19 severity.Molecular medicine (Cambridge, Mass.) · 2026Article
- Osteoarthritis and dementia: contrasting disorders driven by mutual pathways of autophagy, mTOR, GLP-1, AMPK, Wnt, and WISP1.Expert review of clinical pharmacology · 2026Review
- Cyclosporine A rescues the influenza virus fusion with IFITM3-expressing cells by relocating the restriction factor to intraluminal vesicles of multivesicular bodies.Journal of virology · 2026Article
- TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade.Nature communications · 2026Article
- TGF-β-induced autophagy in pulmonary artery endothelial cells associated with chronic thromboembolic pulmonary hypertension.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Intranasal administration of broad-spectrum macrocyclic peptide inhibitor protects against SARS-CoV-2 Omicron variants.Nature communications · 2026Article
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- Evolution of a fuzzy ribonucleoprotein complex in viral assembly.bioRxiv : the preprint server for biology · 2025Article
- Combined effects of restriction factors and transduction adjuvants on lentiviral vector gene transfer efficacy.Scientific reports · 2025Article
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- IFITM1 and IFITM3 cooperate to restrict virus entry in endolysosomes.bioRxiv : the preprint server for biology · 2025Article
- ELV-N34, RvD6-Isomer, or NPD1 Halt Replication of SARS-CoV-2 Omicron BA.5 Virus in Human Lung and Nasal Cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Risk factor analysis and outcomes of heart transplant recipients infected by COVID-19.Frontiers in immunology · 2025Observational
- Attenuation of IFITM proteins' antiviral activity through sequestration into intraluminal vesicles of late endosomes.Frontiers in immunology · 2025Article
- Innate immune control of influenza virus interspecies adaptation via IFITM3.Nature communications · 2024Article
- A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist.PLoS biology · 2024Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 1 country.
Funding
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunocompromised individuals is associated with prolonged virus shedding and evolution of viral variants. Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA approved as mTOR inhibitors for the treatment of human diseases, including cancer and autoimmunity. Rapalog use is commonly associated with an increased susceptibility to infection, which has been traditionally explained by impaired adaptive immunity. Here, we show that exposure to rapalogs increased susceptibility to SARS-CoV-2 infection in tissue culture and in immunologically naive rodents by antagonizing the cell-intrinsic immune response. We identified 1 rapalog (ridaforolimus) that was less potent in this regard and demonstrated that rapalogs promote spike-mediated entry into cells, by triggering the degradation of the antiviral proteins IFITM2 and IFITM3 via an endolysosomal remodeling program called microautophagy. Rapalogs that increased virus entry inhibited mTOR-mediated phosphorylation of the transcription factor TFEB, which facilitated its nuclear translocation and triggered microautophagy. In rodent models of infection, injection of rapamycin prior to and after virus exposure resulted in elevated SARS-CoV-2 replication and exacerbated viral disease, while ridaforolimus had milder effects. Overall, our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating lysosome-mediated suppression of intrinsic immunity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.