Department of Biological Sciences, Moravian College, Bethlehem, Pennsylvania, United States of America.
PLoS One. 2020 Sep 3;15(9):e0238174. doi: 10.1371/journal.pone.0238174. eCollection 2020.
Burkholderia pseudomallei is a facultative intracellular pathogen and the causative agent of melioidosis, a potentially life-threatening disease endemic in Southeast Asia and Northern Australia. Treatment of melioidosis is a long and costly process and the pathogen is inherently resistant to several classes of antibiotics, therefore there is a need for new treatments that can help combat the pathogen. Previous work has shown that the combination of interferon-gamma, an immune system activator, and the antibiotic ceftazidime synergistically reduced the bacterial burden of RAW 264.7 macrophages that had been infected with either B. pseudomallei or Burkholderia thailandensis. The mechanism of the interaction was found to be partially dependent on interferon-gamma-induced production of reactive oxygen species inside the macrophages. To further confirm the role of reactive oxygen species in the effectiveness of the combination treatment, we investigated the impact of the antioxidant and reactive oxygen species scavenger, seleno-L-methionine, on intracellular and extracellular bacterial burden of the infected macrophages. In a dose-dependent manner, high concentrations of seleno-L-methionine (1000 μM) were protective towards infected macrophages, resulting in a reduction of bacteria, on its own, that exceeded the reduction caused by the antibiotic alone and rivaled the effect of ceftazidime and interferon-gamma combined. Seleno-L-methionine treatment also resulted in improved viability of infected macrophages compared to untreated controls. We show that the protective effect of seleno-L-methionine was partly due to its inhibition of bacterial growth. In summary, our study shows a role for high dose seleno-L-methionine to protect and treat macrophages infected with B. thailandensis.
类鼻疽伯克霍尔德菌是一种兼性细胞内病原体，也是类鼻疽病的病原体，类鼻疽病是一种潜在的危及生命的疾病，流行于东南亚和澳大利亚北部。类鼻疽病的治疗是一个漫长而昂贵的过程，病原体对几类抗生素具有固有耐药性，因此需要新的治疗方法来对抗病原体。先前的工作表明，干扰素-γ（一种免疫系统激活剂）和抗生素头孢他啶的联合使用协同降低了 RAW 264.7 巨噬细胞中感染了类鼻疽伯克霍尔德菌或泰国伯克霍尔德菌的细菌负担。发现这种相互作用的机制部分依赖于干扰素-γ诱导巨噬细胞内产生活性氧物质。为了进一步证实活性氧物质在联合治疗效果中的作用，我们研究了抗氧化剂和活性氧物质清除剂硒代-L-蛋氨酸对感染巨噬细胞内和细胞外细菌负担的影响。以剂量依赖性方式，高浓度硒代-L-蛋氨酸（1000 μM）对感染的巨噬细胞具有保护作用，单独使用可减少细菌，其减少量超过单独使用抗生素的减少量，并与头孢他啶和干扰素-γ联合使用的效果相当。硒代-L-蛋氨酸处理还导致感染的巨噬细胞的活力比未处理的对照提高。我们表明，硒代-L-蛋氨酸的保护作用部分归因于其对细菌生长的抑制。总之，我们的研究表明，高剂量硒代-L-蛋氨酸在保护和治疗感染泰国伯克霍尔德菌的巨噬细胞方面发挥了作用。
