Dimethyl fumarate eliminates differentially culturable Mycobacterium tuberculosis in an intranasal murine model of tuberculosis.
Dimethyl fumarate eliminates differentially culturable Mycobacterium tuberculosis in an intranasal murine model of tuberculosis.
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DOI：
10.3389/fcimb.2022.957287
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发表时间：
2022
影响因子：
5.7
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中科院分区：
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结核病每年夺去近150万人的生命。目前的结核病治疗需要联合使用几种药物至少6个月。结核分枝杆菌（Mtb）是结核病的病原体，可在受感染的人类和动物体内持续存在数十年。此外，在感染期间，Mtb产生差异可培养细菌（DCB），其在标准培养基中不生长，但可以在补充有无菌Mtb培养物或重组复苏促进因子（Rpfs）的液体培养基中复苏。在这里，我们证明，在鼻内小鼠模型的结核病，结核分枝杆菌DCB是可检测的肺部感染4周后，其负载在很大程度上保持不变，在进一步的8周。用富马酸二甲酯（DMF）（一种具有免疫调节特性的已知药物）治疗感染小鼠8周，可从肺和脾中清除Mtb DCB。由利福平、异烟肼和吡嗪酰胺组成的标准TB治疗8周可将Mtb负荷降低近4个数量级，但不能根除DCB。然而，DMF、利福平、异烟肼和吡嗪酰胺治疗8周后，在肺和脾中未检测到DCB。我们的数据表明，在标准治疗方案中添加批准的抗炎药物可能会改善结核病治疗并缩短治疗时间。
Tuberculosis (TB) claims nearly 1.5 million lives annually. Current TB treatment requires a combination of several drugs administered for at least 6 months. Mycobacterium tuberculosis (Mtb), the causative agent of TB, can persist in infected humans and animals for decades. Moreover, during infection, Mtb produces differentially culturable bacteria (DCB) that do not grow in standard media but can be resuscitated in liquid media supplemented with sterile Mtb culture filtrates or recombinant resuscitation-promoting factors (Rpfs). Here, we demonstrate that, in an intranasal murine model of TB, Mtb DCB are detectable in the lungs after 4 weeks of infection, and their loads remain largely unchanged during a further 8 weeks. Treatment of the infected mice with dimethyl fumarate (DMF), a known drug with immunomodulatory properties, for 8 weeks eliminates Mtb DCB from the lungs and spleens. Standard TB treatment consisting of rifampicin, isoniazid, and pyrazinamide for 8 weeks reduces Mtb loads by nearly four orders of magnitude but does not eradicate DCB. Nevertheless, no DCB can be detected in the lungs and spleens after 8 weeks of treatment with DMF, rifampicin, isoniazid, and pyrazinamide. Our data suggest that addition of approved anti-inflammatory drugs to standard treatment regimens may improve TB treatment and reduce treatment duration.