Investigating the Role of Everolimus in mTOR Inhibition and Autophagy Promotion as a Potential Host-Directed Therapeutic Target in Mycobacterium tuberculosis Infection

Abstract

Tuberculosis (TB) is a serious infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). The current therapy consists of a combination of antibiotics over the course of four months. Current treatment protocols run into problems due to the growing antibiotic resistance of Mtb and poor compliance to the multi-drug-resistant TB treatment protocol. New treatments are being investigated that target host intracellular processes that could be effective in fighting Mtb infections. Autophagy is an intracellular process that is involved in eliminating cellular debris, as well as intracellular pathogens. Mammalian target of rapamycin (mTOR) is an enzyme involved in inhibiting this pathway. Modulation of mTOR and the autophagy cellular machinery are being investigated as potential therapeutic targets for novel Mtb treatments. In this review, we discuss the background of Mtb pathogenesis, including its interaction with the innate and adaptive immune systems, the mTOR and autophagy pathways, the interaction of Mtb with these pathways, and finally, the drug everolimus, which targets these pathways and is a potential novel therapy for TB treatment.

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

“…Upon detection of microorganisms inside the undamaged vacuole by Toll‐like receptors (TLRs), LC3/GABARAP can become directly conjugated to the limiting membrane of the bacterium‐containing vacuole in a process termed LC3‐assisted phagocytosis. Conjugation of LC3/GABARAP to pathogen‐containing vacuoles promotes content degradation by enhancing lysosomal fusion . Autophagy assists in the secretion of antimicrobial peptides and proteins and intracellular viral restriction factors.…”

“…Conjugation of LC3/GABARAP to pathogencontaining vacuoles promotes content degradation by enhancing lysosomal fusion. [24][25][26][27] Autophagy assists in the secretion of antimicrobial peptides and proteins and intracellular viral restriction factors. For instance, several reports revealed that some populations of tuberculosis patients display polymorphisms in genes linked to the autophagy pathway, namely, the human immunity-related GTPase M, type III interferon γ (IFNγ), IFN-γ receptor, endosomal TLR8, Vitamin D3, and ATP receptor P2X7R, suggesting that some individuals might be more prone to develop tuberculosis due to a defective autophagic response.…”

The anti-tubercular activity of simvastatin is mediated by cholesterol-dependent regulation of autophagy via the AMPK-mTORC1-TFEB axis

“…Since TFEB directly regulates autophagy-inducing effector functions, compounds targeting TFEB may exhibit fewer pleiotropic effects – and presumably fewer unwanted side effects -- than those targeting upstream factors like mTORC1. Indeed, everolimus, a rapamycin-analog (69) that is under consideration for use in host-directed therapy against tuberculosis (70), may cause immunosuppression (71) and facilitate reactivation of latent M. tuberculosis infection (72). Thus, further investigation will be needed to determine the therapeutic dose of everolimus and the optimal mode of its delivery.…”

Prevention of renal ischemia and reperfusion injury by penehyclidine hydrochloride through autophagy activation

“…rapa is an inhibitor of mTor that can be activated by hypoxia or roS directly or indirectly through the activation of aKT signaling (40)(41)(42)(43). The activation of mTor inhibits the expression of aTGs and the formation of autophagosomes (40,41); hypoxia-induced autophagy has been reported in iri (42,43). Wang et al (17) demonstrated that PHC significantly suppressed renal iri through suppressing MaPK, caspase-3 and nF-κB protein activity.…”