Simvastatin Enhances the Immune Response Against Mycobacterium tuberculosis
Simvastatin Enhances the Immune Response Against Mycobacterium tuberculosis
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DOI：
10.3389/fmicb.2019.02097
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发表时间：
2019-09-20
影响因子：
5.2
通讯作者：
Sifuentes-Osornio, Jose
中科院分区：
文献类型：
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作者：
Del Carmen Guerra-De-Blas, Paola;Bobadilla-Del-Valle, Miriam;Sifuentes-Osornio, Jose
结核病仍然是全世界的严重威胁。因此，有必要找到能够缩短治疗时间、增强宿主免疫系统和/或减少感染造成的损害的药物。他汀类药物是降低血浆胆固醇水平并具有免疫调节、抗炎和抗菌作用的药物。尽管有证据表明他汀类药物可能有助于遏制结核分枝杆菌感染，但其对外周血单核细胞（PBMC）参与免疫反应的影响此前尚未被描述。使用 10 名感染结核分枝杆菌 H37Rv 的健康受试者的 PBMC，我们在体外实验模型中分析了辛伐他汀对治疗感染的效果。对结核分枝杆菌生长（以 CFU/mL 为单位）进行直接定量。通过多色流式细胞术评估表型和细胞活化。通过细胞因子珠阵列测定培养物上清液细胞因子水平。通过流式细胞术和共聚焦显微镜评估细胞凋亡和自噬的诱导。辛伐他汀可减少PBMC中结核分枝杆菌的生长，增加培养物中NKT细胞的比例，增加单核细胞中共刺激分子的表达，促进细胞因子IL-1β和IL-12p70的分泌，并激活单核细胞中的凋亡和自噬，从而导致细菌负荷显着降低。我们还观察到 IL-10 产量增加。我们没有观察到任何直接的抗分枝杆菌活性。这项研究为辛伐他汀减少受感染 PBMC 中分枝杆菌负荷的机制提供了新的见解。这些结果表明，辛伐他汀激活了多种有利于遏制结核分枝杆菌感染的免疫机制，为考虑将他汀类药物作为针对宿主的治疗候选药物提供了相关证据。他们还建议，未来的研究需要确定他汀类药物诱导的抗炎机制在结核病治疗中的作用。
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-1 beta 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.