PT  - JOURNAL ARTICLE
AU  - Guoli Shi
AU  - Abhilash I. Chiramel
AU  - Saliha Majdoul
AU  - Kin Kui Lai
AU  - Sudipto Das
AU  - Paul A. Beare
AU  - Thorkell Andresson
AU  - Sonja M. Best
AU  - Alex A. Compton
TI  - Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2
AID  - 10.1101/2021.04.15.440067
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.15.440067
4099  - http://biorxiv.org/content/early/2021/04/16/2021.04.15.440067.short
4100  - http://biorxiv.org/content/early/2021/04/16/2021.04.15.440067.full
AB  - Infection by SARS-CoV-2 generally causes mild symptoms but can lead to severe disease and death in certain populations, including the immunocompromised. Drug repurposing efforts are underway to identify compounds that interfere with SARS-CoV-2 replication or the immunopathology it can elicit. Rapamycin is among those being currently tested in clinical trials for impacts on COVID-19 severity. While rapamycin and rapamycin analogs (rapalogs) are FDA-approved for use as mTOR inhibitors in multiple clinical settings, including cancer, we previously found that rapamycin can increase the susceptibility of cells to infection by Influenza A virus. In this study, we tested the impact of rapalogs on cellular susceptibility to SARS-CoV-2 infection. We report that rapamycin and rapalogs increased SARS-CoV-2 titers in human cervical epithelial and lung epithelial cell lines to different extents, and a similar pattern of enhancement was observed using pseudovirus incorporating viral fusion proteins from SARS-CoV-2, SARS-CoV, MERS, and Influenza A Virus. Rapalogs also promoted cell entry driven by SARS-CoV-2 Spike in nasal cells and primary small airway cells, representing proximal and distal ends of the human respiratory tract, respectively. Interestingly, cell entry enhancement by the rapalog ridaforolimus was cell type-dependent, revealing a previously unrecognized functional divergence between rapalogs. The differential activity of rapalogs was associated with their capacity to induce the degradation of interferon-inducible transmembrane (IFITM) proteins, restriction factors that broadly inhibit virus infection. Our findings will spur the development of mTOR inhibitors that do not suppress the cell’s first line of antiviral defense.Significance Due to a lack of effective antivirals available to combat SARS-CoV-2 infection and the disease it causes (COVID-19), existing drugs that are clinically-approved for use in humans are being considered for deployment during this protracted pandemic. Rapamycin is an immunosuppressant that is administered to humans suffering from cancer, autoimmunity, atherosclerosis, and organ transplant rejection. While generally recognized for its inhibitory effects on the adaptive immune response, we previously showed that rapamycin can also impair intrinsic immunity, the immune system present within all cells of the body. Here, we show that rapamycin and rapamycin analogs (rapalogs) promote the first step of the SARS-CoV-2 infection cycle—entry into cells—by inducing the destruction of antiviral proteins that stand guard during virus invasion.Competing Interest StatementThe authors have declared no competing interest.