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Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2
Guoli Shi, … , Jacob S. Yount, Alex A. Compton
Guoli Shi, … , Jacob S. Yount, Alex A. Compton
Published October 20, 2022
Citation Information: J Clin Invest. 2022;132(24):e160766. https://doi.org/10.1172/JCI160766.
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Research Article Article has an altmetric score of 11

Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2

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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.

Authors

Guoli Shi, Abhilash I. Chiramel, Tiansheng Li, Kin Kui Lai, Adam D. Kenney, Ashley Zani, Adrian C. Eddy, Saliha Majdoul, Lizhi Zhang, Tirhas Dempsey, Paul A. Beare, Swagata Kar, Jonathan W. Yewdell, Sonja M. Best, Jacob S. Yount, Alex A. Compton

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Figure 8

Rapamycin injection into hamsters intensifies viral disease during SARS-CoV-2 infection.

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Rapamycin injection into hamsters intensifies viral disease during SARS-...
(A) Golden Syrian hamsters were injected intraperitoneally with 3 mg/kg rapamycin, ridaforolimus, or an equivalent amount of DMSO (n = 4 animals per group). Four hours later, hamsters were infected intranasally with 6 × 103 PFU SARS-CoV-2. On post-infection day 2, half of the animals received a second injection of rapamycin, ridaforolimus, or DMSO. Oral swabs were taken and used for measurement of oral viral RNA load by RT-qPCR. On post-infection day 10 (or earlier if more than 20% weight loss or agonal breathing was detected), hamsters were euthanized, and lungs were harvested for determination of infectious virus titers by TCID50 assay and IL-6 ELISA. (B) Individual body weight trajectories for each treatment group are plotted by day post-infection. Red lines indicate animals that required euthanasia at humane endpoints (more than 20% weight loss or agonal breathing). (C) Kaplan-Meier survival curves were generated according to the dates of euthanasia (or in 1 case, when the animal was found dead). (D) Infectious virus titers in lungs were determined by TCID50 in Vero-TMPRSS2 cells. Data are depicted as floating bars (minimum, maximum, and mean are shown). (E) Viral RNA copy numbers were determined by RT-qPCR from oral swab 2 days after infection. Data are depicted as box-and-whisker plots. (F) IL-6 protein levels in lungs were determined using a hamster IL-6 ELISA kit. Statistical analysis in C was performed by comparing survival curves between rapamycin and DMSO or ridaforolimus and DMSO treatments using the log-rank (Mantel-Cox) test. Statistical analysis in D was performed by comparing all individual animals (survivors and euthanized) in the rapamycin and ridaforolimus treatment groups using the Mann-Whitney U test. Statistical analysis in E and F was performed by 1-way ANOVA. *P < 0.05 and **P < 0.01. Illustration created with BioRender.com.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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