Department of Biological Sciences, Northern Arizona University, Flagstaff, Arizona, United States of America.
The Pathogen & Microbiome Institute (PMI), Northern Arizona University, Flagstaff, Arizona, United States of America.
PLoS One. 2018 Nov 28;13(11):e0208061. doi: 10.1371/journal.pone.0208061. eCollection 2018.
Binge drinking, an increasingly common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its effects on the immune system's ability to defend against infectious agents are poorly understood. Burkholderia pseudomallei, the causative agent of melioidosis can occur in healthy humans, yet binge alcohol use is progressively being recognized as a major risk factor. Although our previous studies demonstrated that binge alcohol exposure results in reduced alveolar macrophage function and increased Burkholderia virulence in vitro, no experimental studies have investigated the outcomes of binge alcohol on Burkholderia spp. infection in vivo.
In this study, we used the close genetic relatives of B. pseudomallei, B. thailandensis E264 and B. vietnamiensis, as useful BSL-2 model systems. Eight-week-old female C57BL/6 mice were administered alcohol comparable to human binge drinking episodes (4.4 g/kg) or PBS intraperitoneally 30 min before a non-lethal intranasal infection. In an initial B. thailandensis infection (3 x 105), bacteria accumulated in the lungs and disseminated to the spleen in alcohol administered mice only, compared with PBS treated mice at 24 h PI. The greatest bacterial load occurred with B. vietnamiensis (1 x 106) in lungs, spleen, and brain tissue by 72 h PI. Pulmonary cytokine expression (TNF-α, GM-CSF) decreased, while splenic cytokine (IL-10) increased in binge drunk mice. Increased lung and brain permeability was observed as early as 2 h post alcohol administration in vivo. Trans-epithelial electrical resistance (TEER) was significantly decreased, while intracellular invasion of non-phagocytic cells increased with 0.2% v/v alcohol exposure in vitro.
Our results indicate that a single binge alcohol dose suppressed innate immune functions and increased the ability of less virulent Burkholderia strains to disseminate through increased barrier permeability and intracellular invasion of non-phagocytic cells.
binge drinking（狂饮）是一种越来越常见的饮酒形式，与死亡率和发病率的增加有关；然而，它对免疫系统抵御感染因子的能力的影响还知之甚少。 Burkholderia pseudomallei（类鼻疽伯克霍尔德菌）是类鼻疽病的病原体，可在健康人群中出现，然而， binge alcohol use（狂饮酒精）正逐渐被认为是一个主要的危险因素。尽管我们之前的研究表明， binge alcohol exposure（狂饮酒精暴露）会导致肺泡巨噬细胞功能下降，并增加体外 Burkholderia 的毒力，但没有实验研究调查 binge alcohol 对体内 Burkholderia spp.（伯克霍尔德菌属）感染的影响。
在这项研究中，我们使用了 B. pseudomallei 的近亲 B. thailandensis E264 和 B. vietnamiensis，作为有用的 BSL-2 模型系统。八周龄的雌性 C57BL/6 小鼠接受相当于人类 binge drinking episodes（狂饮酒精）的酒精（4.4 g/kg）或 PBS 腹膜内注射，在非致死性鼻内感染前 30 分钟。在初始的 B. thailandensis 感染（3 x 105）中，与 PBS 处理的小鼠相比，只有在给予酒精的小鼠中，细菌在肺部积聚并播散到脾脏，在感染后 24 小时。在感染后 72 小时，肺部、脾脏和脑组织中的细菌负荷最大，为 B. vietnamiensis（1 x 106）。在 binge 醉酒小鼠中，肺部细胞因子表达（TNF-α，GM-CSF）减少，而脾脏细胞因子（IL-10）增加。在体内给予酒精后 2 小时即可观察到肺和脑通透性增加。跨上皮电阻（TEER）明显降低，而体外暴露于 0.2% v/v 酒精可增加非吞噬细胞的细胞内入侵。
我们的结果表明，单次 binge alcohol 剂量可抑制固有免疫功能，并通过增加屏障通透性和非吞噬细胞的细胞内入侵，增加低毒力 Burkholderia 菌株的播散能力。
