Collin Filley

Introduction. Mycobacterium tuberculosis (Mtb) is an organism that causes the disease tuberculosis, a droplet transmitted infection that killed over 1.5 million people in 2018.¹ Mtb infection is spread throughout the world with highest prevalence in Africa and Southeast Asia.² Tuberculosis is classically treated by a rifampicin, isoniazid, pyrazinamide, and ethambutol, but modern infections have begun to exhibit resistance which creates a need to seek alternative treatments. HMG-CoA reductase inhibitors, or statins, exhibit anti-mycobacterial effects and may be useful against tuberculosis. Researchers hypothesize that the mechanism of these effects is through reversal of infection-mediated decreases in autophagy, or “self-eating,” a process by which cells remove their dysfunctional components.¹  Methods. Human THP-1 cells were infected with Mtb and then treated with simvastatin. Western blot analysis was done to determine autophagic protein levels present in the infected cells both pre and post simvastatin treatment.³ Results. P62, a biomarker that is elevated when autophagy is impaired, increased 300% when the THP-1 cells were infected with Mtb. Upon simvastatin treatment, the P62 levels decreased to half the level of the infected cells indicating that the inhibition of autophagy was reversed. This reduction was reversed by the addition of exogenous cholesterol, indicating that the anti-cholesterol effects of the statin, specifically, resulted in the decrease in P62 levels. Mtb infection also activates MTORC1, which is an inhibitor of autophagy. Simvastatin treatment decreased MTORC1 levels. This reduction in MTORC1 was shown to be reversible by the addition of L-arginine, which is a known activator of MTORC1. AMPK, an inhibitor of MTORC1 and an inducer of autophagy, was downregulated with infection and was upregulated by the simvastatin treatment. This upregulation was also reversed by the addition of exogenous cholesterol.³ Conclusion. Mtb infection downregulates autophagy activators and upregulates autophagy inhibitors, which facilitates intracellular persistence. Autophagy serves to remove the dysfunctional cellular machinery once a cell is invaded often leading to apoptosis, but Mtb inhibits this process allowing for a long-term infection. The ability of a statin to reverse these anti-autophagic effects is an exciting prospect in the treatment of Mtb infections. These developments have led to an ongoing clinical trial using pravastatin to treat Mtb.⁴

1. Tahir F, Bin Arif T, Ahmed J, Shah SR, Khalid M. Anti-tuberculous Effects of Statin Therapy: A Review of Literature. Cureus. 2020;12(3):e7404. Published 2020 Mar 25. doi:10.7759/cureus.7404
2. MacNeil A, Glaziou P, Sismanidis C, Maloney S, Floyd K. Global Epidemiology of Tuberculosis and Progress Toward Achieving Global Targets — 2017. MMWR Morb Mortal Wkly Rep 2019;68:263–266DOI: http://dx.doi.org/10.15585/mmwr.mm6811a3
3. Bruiners N, Dutta NK, Guerrini V, et al. The anti-tubercular activity of simvastatin is mediated by cholesterol-driven autophagy via the AMPK-mTORC1-TFEB axis. J Lipid Res. 2020;61(12):1617-1628. doi:10.1194/jlr.RA120000895
4. StAT-TB (Statin Adjunctive Therapy for TB): A Phase 2b Dose-finding Study of Pravastatin in Adults With Tuberculosis. ClinicalTrials.gov identifier: NCT03882177. https://clinicaltrials.gov/ct2/show/NCT03882177. Updated June 9, 2020. Accessed May 17, 2021