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.
Highlights
Treatment for susceptible tuberculosis involves the administration of several drugs over a 6 month period, which can be extended for up to 18 months for multidrug-resistant tuberculosis (World Health Organization [WHO], 2018)
It was observed that peripheral blood mononuclear cells (PBMCs) that were infected and incubated for 96 h and treated with 1 μM simvastatin or 1 μM simvastatin acid, exhibited reduced bacterial loads compared to those of the control cells and/or those treated with the vehicle
We described the effects of simvastatin on PBMCs in general and in terms of specific cell subtypes
Summary
Treatment for susceptible tuberculosis involves the administration of several drugs over a 6 month period, which can be extended for up to 18 months for multidrug-resistant tuberculosis (World Health Organization [WHO], 2018). It has been proposed that drugs that modify the host immune response to infection rather than drugs directly acting against the pathogen may be more effective for treatment This type of drug treatment is known as host-directed therapy. Using host-directed therapies as an adjunct to standard anti-TB treatment could reduce the infection duration and eventually lead to decreased relapse rates (Machelart et al, 2017). These types of drugs, including rapamycin, metformin, valproic acid, ibuprofen, and statins, have been shown to affect the growth of mycobacteria in infected cells in in vitro studies (Schiebler et al, 2015; Zumla et al, 2015)
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