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

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It’s worth thinking about, especially in the first couple of days after an intermittent dose. Most such doses are far below the daily doses for therapeutic immune suppression, and smaller doses might or might not increase entry into the cell.

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Yeah, lately I had been feeling complacent thinking that rapamycin only causes issues with bacterial infections and not viral infections.

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Wow, good to know! Thanks for posting that. Definitely argues for wearing a quality N95 mask or equivalent when around others, especially in the first few days after a dose.


Final Paper that was published:

(@Agetron something to be aware of related to higher doses vs. lower doses).

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 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 naive rodents by antagonizing the cell-intrinsic immune response. By identifying one rapalog (ridaforolimus) that is less potent in this regard, we demonstrate that rapalogs promote Spike-mediated entry into cells by triggering the degradation of antiviral proteins IFITM2 and IFITM3 via an endolysosomal remodeling program called microautophagy. Rapalogs that increase 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 lysosome-mediated suppression of intrinsic immunity.

I think this section of the paper is useful and demonstrates that the conclusions in the paper relate to much higher dosages and dosing frequencies:

The injection dose of rapamycin or ridaforolimus (3 mg/kg) that we administered to hamsters and mice, when adjusted for body surface area and an average human weight of 60 kg (58), equates to approximately 15 mg per human. This figure is similar to those administered to humans in clinical settings, such as the use of rapamycin for the treatment of glioblastoma (up to 10 mg daily for multiple days), the use of temsirolimus for the treatment of renal cell carcinoma (25 mg once weekly), or the use of everolimus for the treatment of tuberous sclerosis (TS), a genetic disorder resulting in hyperactivation of mTOR (10 mg daily, continuously) (23, 59-61).

Interestingly, a case report detailed the deaths of two TS patients (a father and daughter) who, despite discontinuing everolimus upon detection of SARS-CoV-2 infection, died from severe COVID-19 in late 2020 (61). Our findings detailing the suppression of cell-intrinsic immunity by rapalogs raise the possibility that their use may predispose individuals to SARS-CoV-2 infection and severe forms of COVID-19.

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


PDF for download:



I appreciate the heads up… staying at 6mg plus a cup of fresh squeezed Pink Grapefruit juice. Should put me at 30 ng/mL.

Will do blood test in November rapamycin trough and 2.5 hours later… the 6mg plus GFJ… for cmax and see if consistent.

Definitely watching my health… while on rapamycin.