Simvastatin Enhances the Immune Response Against Mycobacterium tuberculosis

Paola Del Carmen Guerra-De-Blas, Miriam Bobadilla-Del-Valle, Isabel Sada-Ovalle, Iris Estrada-García, Pedro Torres-González, Alejandro López-Saavedra, Silvia Guzmán-Beltrán, Alfredo Ponce-de-León, José Sifuentes-Osornio

Research output: Contribution to journalArticle

Abstract

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 the damage caused by the infection. Statins are drugs that reduce plasma cholesterol levels and 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 have not been previously described. Using PBMCs from 10 healthy subjects infected with M. tuberculosis H37Rv, we analyzed the effects of simvastatin on the treatment of the infections in an in vitro experimental model. Direct quantification of M. tuberculosis growth (in CFU/mL) was performed. Phenotypes and cell activation were assessed via multi-color flow cytometry. Culture supernatant cytokine levels were determined via cytokine bead arrays. The induction of apoptosis and autophagy was evaluated via 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, resulting in a significant reduction in bacterial load. We also observed an increase in IL-10 production. We did not observe any direct antimycobacterial activity. This study provides new insight into the mechanism through which simvastatin reduces the mycobacterial load in infected PBMCs. These results demonstrate that simvastatin activates several immune mechanisms that favor the containment of M. tuberculosis infection, providing relevant evidence to consider statins as candidates for host-directed therapy. They also suggest that future studies are needed to define the roles of statin-induced anti-inflammatory mechanisms in tuberculosis treatment.

Original languageEnglish (US)
Article number2097
JournalFrontiers in Microbiology
Volume10
DOIs
StatePublished - Sep 20 2019

Fingerprint

Simvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Mycobacterium tuberculosis
Blood Cells
Mycobacterium Infections
Autophagy
Cytokines
Monocytes
Flow Cytometry
Tuberculosis
Anti-Inflammatory Agents
Apoptosis
Natural Killer T-Cells
Bacterial Load
Therapeutics
Growth
Infection
Interleukin-1
Confocal Microscopy
Interleukin-10

Keywords

  • apoptosis
  • autophagy
  • cytokines
  • host directed therapy
  • immune response
  • simvastatin
  • tuberculosis

ASJC Scopus subject areas

  • Microbiology
  • Microbiology (medical)

Cite this

Guerra-De-Blas, P. D. C., Bobadilla-Del-Valle, M., Sada-Ovalle, I., Estrada-García, I., Torres-González, P., López-Saavedra, A., ... Sifuentes-Osornio, J. (2019). Simvastatin Enhances the Immune Response Against Mycobacterium tuberculosis. Frontiers in Microbiology, 10, [2097]. https://doi.org/10.3389/fmicb.2019.02097

Simvastatin Enhances the Immune Response Against Mycobacterium tuberculosis. / Guerra-De-Blas, Paola Del Carmen; Bobadilla-Del-Valle, Miriam; Sada-Ovalle, Isabel; Estrada-García, Iris; Torres-González, Pedro; López-Saavedra, Alejandro; Guzmán-Beltrán, Silvia; Ponce-de-León, Alfredo; Sifuentes-Osornio, José.

In: Frontiers in Microbiology, Vol. 10, 2097, 20.09.2019.

Research output: Contribution to journalArticle

Guerra-De-Blas, PDC, Bobadilla-Del-Valle, M, Sada-Ovalle, I, Estrada-García, I, Torres-González, P, López-Saavedra, A, Guzmán-Beltrán, S, Ponce-de-León, A & Sifuentes-Osornio, J 2019, 'Simvastatin Enhances the Immune Response Against Mycobacterium tuberculosis', Frontiers in Microbiology, vol. 10, 2097. https://doi.org/10.3389/fmicb.2019.02097
Guerra-De-Blas PDC, Bobadilla-Del-Valle M, Sada-Ovalle I, Estrada-García I, Torres-González P, López-Saavedra A et al. Simvastatin Enhances the Immune Response Against Mycobacterium tuberculosis. Frontiers in Microbiology. 2019 Sep 20;10. 2097. https://doi.org/10.3389/fmicb.2019.02097
Guerra-De-Blas, Paola Del Carmen ; Bobadilla-Del-Valle, Miriam ; Sada-Ovalle, Isabel ; Estrada-García, Iris ; Torres-González, Pedro ; López-Saavedra, Alejandro ; Guzmán-Beltrán, Silvia ; Ponce-de-León, Alfredo ; Sifuentes-Osornio, José. / Simvastatin Enhances the Immune Response Against Mycobacterium tuberculosis. In: Frontiers in Microbiology. 2019 ; Vol. 10.
@article{0b3b8aba67f045d2b82634aaff65bd9d,
title = "Simvastatin Enhances the Immune Response Against Mycobacterium tuberculosis",
abstract = "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 the damage caused by the infection. Statins are drugs that reduce plasma cholesterol levels and 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 have not been previously described. Using PBMCs from 10 healthy subjects infected with M. tuberculosis H37Rv, we analyzed the effects of simvastatin on the treatment of the infections in an in vitro experimental model. Direct quantification of M. tuberculosis growth (in CFU/mL) was performed. Phenotypes and cell activation were assessed via multi-color flow cytometry. Culture supernatant cytokine levels were determined via cytokine bead arrays. The induction of apoptosis and autophagy was evaluated via 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, resulting in a significant reduction in bacterial load. We also observed an increase in IL-10 production. We did not observe any direct antimycobacterial activity. This study provides new insight into the mechanism through which simvastatin reduces the mycobacterial load in infected PBMCs. These results demonstrate that simvastatin activates several immune mechanisms that favor the containment of M. tuberculosis infection, providing relevant evidence to consider statins as candidates for host-directed therapy. They also suggest that future studies are needed to define the roles of statin-induced anti-inflammatory mechanisms in tuberculosis treatment.",
keywords = "apoptosis, autophagy, cytokines, host directed therapy, immune response, simvastatin, tuberculosis",
author = "Guerra-De-Blas, {Paola Del Carmen} and Miriam Bobadilla-Del-Valle and Isabel Sada-Ovalle and Iris Estrada-Garc{\'i}a and Pedro Torres-Gonz{\'a}lez and Alejandro L{\'o}pez-Saavedra and Silvia Guzm{\'a}n-Beltr{\'a}n and Alfredo Ponce-de-Le{\'o}n and Jos{\'e} Sifuentes-Osornio",
year = "2019",
month = "9",
day = "20",
doi = "10.3389/fmicb.2019.02097",
language = "English (US)",
volume = "10",
journal = "Frontiers in Microbiology",
issn = "1664-302X",
publisher = "Frontiers Media S. A.",

}

TY - JOUR

T1 - Simvastatin Enhances the Immune Response Against Mycobacterium tuberculosis

AU - Guerra-De-Blas, Paola Del Carmen

AU - Bobadilla-Del-Valle, Miriam

AU - Sada-Ovalle, Isabel

AU - Estrada-García, Iris

AU - Torres-González, Pedro

AU - López-Saavedra, Alejandro

AU - Guzmán-Beltrán, Silvia

AU - Ponce-de-León, Alfredo

AU - Sifuentes-Osornio, José

PY - 2019/9/20

Y1 - 2019/9/20

N2 - 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 the damage caused by the infection. Statins are drugs that reduce plasma cholesterol levels and 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 have not been previously described. Using PBMCs from 10 healthy subjects infected with M. tuberculosis H37Rv, we analyzed the effects of simvastatin on the treatment of the infections in an in vitro experimental model. Direct quantification of M. tuberculosis growth (in CFU/mL) was performed. Phenotypes and cell activation were assessed via multi-color flow cytometry. Culture supernatant cytokine levels were determined via cytokine bead arrays. The induction of apoptosis and autophagy was evaluated via 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, resulting in a significant reduction in bacterial load. We also observed an increase in IL-10 production. We did not observe any direct antimycobacterial activity. This study provides new insight into the mechanism through which simvastatin reduces the mycobacterial load in infected PBMCs. These results demonstrate that simvastatin activates several immune mechanisms that favor the containment of M. tuberculosis infection, providing relevant evidence to consider statins as candidates for host-directed therapy. They also suggest that future studies are needed to define the roles of statin-induced anti-inflammatory mechanisms in tuberculosis treatment.

AB - 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 the damage caused by the infection. Statins are drugs that reduce plasma cholesterol levels and 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 have not been previously described. Using PBMCs from 10 healthy subjects infected with M. tuberculosis H37Rv, we analyzed the effects of simvastatin on the treatment of the infections in an in vitro experimental model. Direct quantification of M. tuberculosis growth (in CFU/mL) was performed. Phenotypes and cell activation were assessed via multi-color flow cytometry. Culture supernatant cytokine levels were determined via cytokine bead arrays. The induction of apoptosis and autophagy was evaluated via 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, resulting in a significant reduction in bacterial load. We also observed an increase in IL-10 production. We did not observe any direct antimycobacterial activity. This study provides new insight into the mechanism through which simvastatin reduces the mycobacterial load in infected PBMCs. These results demonstrate that simvastatin activates several immune mechanisms that favor the containment of M. tuberculosis infection, providing relevant evidence to consider statins as candidates for host-directed therapy. They also suggest that future studies are needed to define the roles of statin-induced anti-inflammatory mechanisms in tuberculosis treatment.

KW - apoptosis

KW - autophagy

KW - cytokines

KW - host directed therapy

KW - immune response

KW - simvastatin

KW - tuberculosis

UR - http://www.scopus.com/inward/record.url?scp=85072948803&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072948803&partnerID=8YFLogxK

U2 - 10.3389/fmicb.2019.02097

DO - 10.3389/fmicb.2019.02097

M3 - Article

AN - SCOPUS:85072948803

VL - 10

JO - Frontiers in Microbiology

JF - Frontiers in Microbiology

SN - 1664-302X

M1 - 2097

ER -