TY - JOUR T1 - Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2. AU - Shi,Guoli, AU - Chiramel,Abhilash I, AU - Li,Tiansheng, AU - Lai,Kin Kui, AU - Kenney,Adam D, AU - Zani,Ashley, AU - Eddy,Adrian, AU - Majdoul,Saliha, AU - Zhang,Lizhi, AU - Dempsey,Tirhas, AU - Beare,Paul A, AU - Kar,Swagata, AU - Yewdell,Jonathan W, AU - Best,Sonja M, AU - Yount,Jacob S, AU - Compton,Alex A, Y1 - 2022/04/06/ PY - 2021/4/22/pubmed PY - 2021/4/22/medline PY - 2021/4/21/entrez JF - bioRxiv : the preprint server for biology JO - bioRxiv N2 - UNLABELLED: SARS-CoV-2 infection in immunocompromised individuals is associated with prolonged virus shedding and the evolution of viral variants. Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved as mTOR inhibitors in clinical settings such as cancer and autoimmunity. Rapalog use is commonly associated with increased susceptibility to infection, which has been traditionally explained by impaired adaptive immunity. Here, we show that exposure to rapalogs increases susceptibility to SARS-CoV-2 infection in tissue culture and in immunologically naïve rodents by antagonizing the cell-intrinsic immune response. By identifying one rapalog (ridaforolimus) that is less active in this regard, we demonstrate that rapalogs promote Spike-mediated entry into cells by triggering the degradation of IFITM2 and IFITM3 via an endolysosomal remodeling program known as microautophagy. Rapalogs that promote virus entry inhibit the mTOR-mediated phosphorylation of the transcription factor TFEB, which facilitates its nuclear translocation and triggers 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 a lysosome-mediated suppression of intrinsic immunity. SIGNIFICANCE: Rapamycin is an immunosuppressant used in humans to treat cancer, autoimmunity, and other disease states. Here, we show that rapamycin and related compounds promote the first step of the SARS-CoV-2 infection cycle-entry into cells-by disarming cell-intrinsic immune defenses. We outline the molecular basis for this effect by identifying a rapamycin derivative that is inactive, laying the foundation for improved mTOR inhibitors that do not suppress intrinsic immunity. We find that rapamycin analogs that promote SARS-CoV-2 entry are those that activate TFEB, a transcription factor that triggers the degradation of antiviral membrane proteins inside of cells. Finally, rapamycin administration to rodents prior to SARS-CoV-2 challenge results in enhanced viral disease, revealing that its use in humans may increase susceptibility to infection. UR - https://www.unboundmedicine.com/medline/citation/33880473/Rapalogs_downmodulate_intrinsic_immunity_and_promote_cell_entry_of_SARS_CoV_2_ DB - PRIME DP - Unbound Medicine ER -