Primary Lung Dendritic Cell Cultures to Assess Efficacy of Spectinamide-1599 Against Intracellular Mycobacterium tuberculosis.
Primary Lung Dendritic Cell Cultures to Assess Efficacy of Spectinamide-1599 Against Intracellular Mycobacterium tuberculosis.
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DOI：
10.3389/fmicb.2018.01895
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发表时间：
2018
影响因子：
5.2
通讯作者：
Gonzalez-Juarrero M
中科院分区：
文献类型：
--
作者：
Santos K;Lukka PB;Grzegorzewicz A;Jackson M;Trivedi A;Pavan F;Chorilli M;Braunstein M;Hickey A;Meibohm B;Gonzalez-Juarrero M
迫切需要快速、有效、无副作用地治疗结核病。结核分枝杆菌(Mtb)是结核病的病原体，可在巨噬细胞和树突状细胞内长期存活，目前的药物治疗方案难以消除这些胞内细菌。众所周知，结核分枝杆菌对药物治疗的反应取决于其细胞外和细胞内的位置和复制状态。在这项研究中，我们分离和培养了肺来源的树突状细胞，并将其用作细胞内分枝杆菌药物疗效的筛选系统。使用单一或联合药物治疗，我们研究了壮观胺-1599和吡津胺(针对缓慢生长的细菌的抗生素)在杀死位于肺来源的树突状细胞内的细菌方面的作用。此外，由于干扰素-γ是结核分枝杆菌感染时产生的一种基本细胞因子，并存在于结核病化疗中，我们还评估了在存在和不存在干扰素-γ的情况下这些药物的疗效。我们的结果表明，单独使用壮观胺-1599或吡津酰胺可以减少99.9%以上的细胞内细菌负荷。更令人印象深刻的是，用壮观胺-1599和吡津胺与干扰素-γ联合处理TB感染的肺源性树突状细胞时，观察到了很强的协同效应，使细胞内负荷降低到检测下限以下。我们的结论是，肺来源的树突状细胞的干扰素-γ激活对于壮观胺-1599和吡津胺的协同作用是必不可少的。
There is an urgent need to treat tuberculosis (TB) quickly, effectively and without side effects. Mycobacterium tuberculosis (Mtb), the causative organism of TB, can survive for long periods of time within macrophages and dendritic cells and these intracellular bacilli are difficult to eliminate with current drug regimens. It is well established that Mtb responds differentially to drug treatment depending on its extracellular and intracellular location and replicative state. In this study, we isolated and cultured lung derived dendritic cells to be used as a screening system for drug efficacy against intracellular mycobacteria. Using mono- or combination drug treatments, we studied the action of spectinamide-1599 and pyrazinamide (antibiotics targeting slow-growing bacilli) in killing bacilli located within lung derived dendritic cells. Furthermore, because IFN-γ is an essential cytokine produced in response to Mtb infection and present during TB chemotherapy, we also assessed the efficacy of these drugs in the presence and absence of IFN-γ. Our results demonstrated that monotherapy with either spectinamide-1599 or pyrazinamide can reduce the intracellular bacterial burden by more than 99.9%. Even more impressive is that when TB infected lung derived dendritic cells are treated with spectinamide-1599 and pyrazinamide in combination with IFN-γ a strong synergistic effect was observed, which reduced the intracellular burden below the limit of detection. We concluded that IFN-γ activation of lung derived dendritic cells is essential for synergy between spectinamide-1599 and pyrazinamide.
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DOI：
10.1084/jem.158.3.670
发表时间：
1983-09-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Nathan CF;Murray HW;Wiebe ME;Rubin BY
通讯作者：
Rubin BY
影响因子：
4.6
作者：
Aljayyoussi G;Jenkins VA;Sharma R;Ardrey A;Donnellan S;Ward SA;Biagini GA
通讯作者：
Biagini GA
影响因子：
4.4
作者：
Ordway, D;Henao-Tamayo, M;Gonzalez-Juarrero, M
通讯作者：
Gonzalez-Juarrero, M
影响因子：
4.5
作者：
Madhura, Dora Babu;Trivedi, Ashit;Meibohm, Bernd
通讯作者：
Meibohm, Bernd
影响因子：
4.9
作者：
Lanoix, Jean-Philippe;Betoudji, Fabrice;Nuermberger, Eric
通讯作者：
Nuermberger, Eric