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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Microbiol. | doi: 10.3389/fmicb.2019.02097

Simvastatin enhances immune response against Mycobacterium tuberculosis

  • 1Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico
  • 2National Institute of Respiratory Diseases (Mexico), Mexico
  • 3Posgrado en Ciencias en Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico
  • 4National Institute of Cancerology (INCan), Mexico

Tuberculosis remains a serious threat worldwide. For this reason, it is necessary to identify agents that shorten the duration of treatment, strengthen the host immune system, and/or decrease damage caused by the infection. Statins are drugs that reduce plasma cholesterol levels and also have immunomodulatory, anti-inflammatory and antimicrobial effects. Although there is evidence that statins may contribute to the containment of Mycobacterium tuberculosis infection, their effects on peripheral blood mononuclear cells (PBMCs) involved in the immune response has not been previously described. Using PBMCs, from ten healthy subjects, that were infected with M. tuberculosis H37Rv, we analysed the effects of simvastatin on the treatment of infection in an in vitro experimental model. Direct quantification of M. tuberculosis growth in CFU/mL was performed. Phenotype and cell activation were assessed by multi-color flow cytometry. Cytokines levels were determined in culture supernatant by cytokine bead arrays. Induction of apoptosis and autophagy were evaluated by flow cytometry and confocal microscopy. Simvastatin decreased the growth of M. tuberculosis in PBMCs, increased the proportion of NKT cells in culture, increased the expression of co-stimulatory molecules in monocytes, promoted the secretion of the cytokines IL-1β and IL-12p70, and activated apoptosis and autophagy in monocytes, which resulted in a significant reduction of the bacterial load. We also observed an increase in the production of IL-10. We did not observe direct antimycobacterial activity. This study provides new insights into the immune correlates that how simvastatin reduce the mycobacterial load in infected PBMCs. These results demonstrate that simvastatin activates several immune mechanisms that favour the containment of M. tuberculosis infection, providing relevant evidence to consider statins as candidates for host-directed therapy. It also opens the need of future studies to define the role of anti-inflammatory mechanisms induced by statins in the therapy of tuberculosis.

Keywords: Simvastatin, Tuberculosis, immune response, Cytokines, Autophagy, Apoptosis, host directed therapy

Received: 17 Apr 2019; Accepted: 26 Aug 2019.

Copyright: © 2019 Guerra De Blas, Bobadilla, Sada, Estrada-Garcia, Torres, López, Guzman, PONCE-DE-LEON and Sifuentes- Osornio. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. José Sifuentes- Osornio, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City, Mexico, sifuentesosornio@gmail.com