US Army Center for Environmental Health Research, 568 Doughten Drive, Fort Detrick, MD, 21702, USA.
The Geneva Foundation, Fort Detrick, MD, USA.
Metabolomics. 2018 Dec 29;15(1):2. doi: 10.1007/s11306-018-1457-2.
Pneumonic plague is caused by the aerosolized form of Yersinia pestis and is a highly virulent infection with complex clinical consequences, and without treatment, the fatality rate approaches 100%. The exact mechanisms of disease progression are unclear, with limited work done using metabolite profiling to study disease progression.
The aim of this pilot study was to profile the plasma metabolomics in an animal model of Y. pestis infection.
In this study, African Green monkeys were challenged with the highly virulent, aerosolized Y. pestis strain CO92, and untargeted metabolomics profiling of plasma was performed using liquid and gas chromatography with mass spectrometry.
At early time points post-exposure, we found significant increases in polyunsaturated, long chain fatty acid metabolites with p values ranging from as low as 0.000001 (ratio = 1.94) for the metabolite eicosapentaenoate to 0.04 (ratio = 1.36) for the metabolite adrenate when compared to time-matched controls. Multiple acyl carnitines metabolites were increased at earlier time points and could be a result of fatty acid oxidation defects with p values ranging from as low as 0.00001 (ratio = 2.95) for the metabolite octanoylcarnitine to 0.04 (ratio = 1.33) for metabolite deoxycarnitine when compared to time-matched controls. Dicarboxylic acids are important metabolic products of fatty acids oxidation, and when compared to time matched controls, were higher at earlier time points where metabolite tetradecanedioate has a ratio of 4.09 with significant p value of 0.000002 and adipate with a ratio of 1.12 and p value of 0.004. The metabolites from lysolipids (with significant p values ranging from 0.00006 for 1-oleoylglycerophosphoethanolamine to 0.04 for 1-stearoylglycerophosphoethanolamine and a ratio of 0.47 and 0.78, respectively) and bile acid metabolism (with significant p values ranging from 0.02 for cholate to 0.04 for deoxycholate and a ratio of 0.39 and 0.66, respectively) pathways were significantly lower compared to their time-matched controls during the entire course of infection. Metabolite levels from amino acid pathways were disrupted, and a few from the leucine, isoleucine and valine pathway were significantly higher (p values ranging from 0.002 to 0.04 and ratios ranging from 1.3 to 1.5, respectively), whereas metabolites from the urea cycle, arginine and proline pathways were significantly lower (p values ranging from 0.00008 to 0.02 and ratios ranging from 0.5 to 0.7, respectively) during the course of infection.
The involvement of several lipid pathways post-infection suggested activation of pathways linked to inflammation and oxidative stress. Metabolite data further showed increased energy demand, and multiple metabolites indicated potential hepatic dysfunction. Integration of blood metabolomics and transcriptomics data identified linoleate as a core metabolite with cross-talk with multiple genes from various time points. Collectively, the data from this study provided new insights into the mechanisms of Y. pestis pathogenesis that may aid in development of therapeutics.
肺鼠疫是由耶尔森氏鼠疫杆菌的气溶胶形式引起的，是一种具有复杂临床后果的高毒力感染，如果不治疗，死亡率接近 100%。疾病进展的确切机制尚不清楚，使用代谢物分析来研究疾病进展的工作有限。
本初步研究的目的是对 Y. pestis 感染动物模型的血浆代谢组进行分析。
在这项研究中，非洲绿猴受到高毒力、气溶胶化的 Y. pestis 菌株 CO92 的挑战，并使用液相和气相色谱-质谱联用对血浆进行非靶向代谢组学分析。
在暴露后的早期时间点，我们发现多不饱和、长链脂肪酸代谢物的水平显著增加，与时间匹配的对照相比，最低 p 值低至 0.000001（代谢物二十碳五烯酸的比值为 1.94），最高 p 值为 0.04（代谢物肾上腺醇的比值为 1.36）。多种酰基辅酶 A 代谢物在早期时间点增加，可能是脂肪酸氧化缺陷的结果，与时间匹配的对照相比，最低 p 值低至 0.00001（代谢物辛酰基辅酶 A 的比值为 2.95），最高 p 值为 0.04（代谢物脱氧辅氨酸的比值为 1.33）。二羧酸是脂肪酸氧化的重要代谢产物，与时间匹配的对照相比，在早期时间点更高，其中十四烷二酸的比值为 4.09，具有显著的 p 值 0.000002，而己二酸的比值为 1.12，p 值为 0.004。来自溶血磷脂的代谢物（具有显著的 p 值，范围从 1-油酰基甘油磷酸乙醇胺的 0.00006 到 1-硬脂酰基甘油磷酸乙醇胺的 0.04，比值分别为 0.47 和 0.78）和胆汁酸代谢途径（具有显著的 p 值，范围从胆酸盐的 0.02 到脱氧胆酸盐的 0.04，比值分别为 0.39 和 0.66）在整个感染过程中与时间匹配的对照相比明显降低。氨基酸途径的代谢物水平受到干扰，亮氨酸、异亮氨酸和缬氨酸途径的几种代谢物水平显著升高（p 值范围从 0.002 到 0.04，比值范围从 1.3 到 1.5），而尿素循环、精氨酸和脯氨酸途径的代谢物水平显著降低（p 值范围从 0.00008 到 0.02，比值范围从 0.5 到 0.7）在感染过程中。
感染后几种脂质途径的参与表明炎症和氧化应激相关途径的激活。代谢物数据进一步表明能量需求增加，多种代谢物表明潜在的肝功能障碍。血液代谢组学和转录组学数据的整合确定了亚油酸作为具有跨多个时间点与来自各种途径的多个基因相互作用的核心代谢物。总的来说，这项研究的数据提供了鼠疫耶尔森氏菌发病机制的新见解，可能有助于治疗方法的开发。
