Effect of Calcineurin Inhibitors and Mammalian Target of Rapamycin Inhibitors on the Course of COVID-19 in Kidney Transplant Recipients

Abstract

Coronavirus disease 19 (COVID-19) has been an ongoing pandemic since December 2019. Unfortunately, kidney transplant recipients are a high-risk group during the disease course, and scientific data are still limited in this patient group. Beyond the dosage of immunosuppressive drugs, pharmacological immunosuppression may also alter the infection response in the COVID-19 course. The effects of immunosuppressive agents on the development and process of infection should not be decided only by determining how potent they are and how much they suppress the immune system; it is also thought that the direct effect of the virus, increased oxidative stress, and cytokine storm play a role in the pathogenesis of COVID-19 disease. There are data about immunosuppressive drugs like calcineurin inhibitors (CNI) or mammalian target of rapamycin inhibitors (mTORi) therapy related to their beneficial effects during any infection course. Limited data suggest that the use of CNI or mTORi may have beneficial effects on the process. In this hypothetical review, the probable impacts of CNI and mTORi on the pathogenesis of the COVID-19 were investigated.

PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy

“…tacrolimus has shown a more significant inhibitory effect on cellular immune responses than everolimus, but both inhibit humoral immune responses equally. as a result, tacrolimus can be effective in COVID-19 treatment due to its ability to attenuate the production of T-related cytokines [ 5 ]. Oral administration of sapanisertib (INK0128; INK128) blocks mTORC1 and mTORC2 [ 9 ].…”

“…Rapamycin decreases CD19 + CD27 + memory B lymphocytes and induces their differentiation to plasma cells. It is also shown that rapamycin (by inducing HLA-DR expression) was more effective in reducing the population of B lymphocytes than tacrolimus [ 5 ]. In the light of such investigations, it can be concluded that rapamycin can play a role in intervening in the production of antibodies in COVID-19 by reducing the population of B lymphocytes.…”

“…SARS-CoV-2 can improve its survival and replication by dysregulating the PI3K/Akt/mTOR signaling pathway [4]. The onset of SARS-CoV-2 infection generally induces immune-related mechanisms such as oxidative stress and triggers a cytokine storm, leading to severe clinical manifestations in the infected host [5]. The host signaling pathways such as the PI3K/Akt/mTOR pathway can modify the production of pro-inflammatory cytokines (e.g., IL-8) [6].…”

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

“…PRAS40 blocks binding of p70 ribosomal S6 kinase (p70S6K) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) to Raptor that can affect mTORC1 activity [165,166]. Rapamycin mTORC1 [24] as well inhibits activation of mTORC1 [162,[167][168][169][170]. mTORC2 has some different components when compared to mTORC1 [171].…”

Neurodegeneration, memory loss, and dementia: the impact of biological clocks and circadian rhythm

“…mTORC1 activity is controlled through a number of pathways that includes PRAS40 by blocking the association of p70 ribosomal S6 kinase (p70S6K) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) with Raptor [167,168]. Rapamycin is an agent that can inhibit mTOR activity [164,[169][170][171][172]. Rapamycin blocks the activity of mTORC1 through its association with immunophilin FK-506-binding protein 12 (FKBP12) that attaches to the FKBP12 -rapamycin-binding domain (FRB) at the carboxy (C) -terminal of mTOR to impede the FRB domain of mTORC1 [4].…”