Within-host evolution of Burkholderia pseudomallei over a twelve-year chronic carriage infection.
Within-host evolution of Burkholderia pseudomallei over a twelve-year chronic carriage infection.
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DOI：
10.1128/mbio.00388-13
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发表时间：
2013-07-16
期刊：
影响因子：
6.4
通讯作者：
Currie BJ
中科院分区：
文献类型：
--
作者：
Price EP;Sarovich DS;Mayo M;Tuanyok A;Drees KP;Kaestli M;Beckstrom-Sternberg SM;Babic-Sternberg JS;Kidd TJ;Bell SC;Keim P;Pearson T;Currie BJ
假鼻疽伯克霍尔德氏菌导致了一种潜在的致命疾病类鼻疽。人们普遍认为假鼻疽杆菌是一种非共生细菌，任何培养阳性的临床标本都表明疾病需要治疗。在澳大利亚达尔文对类鼻疽病例进行的一项长达23年的研究中，707名幸存者中只有一名患者出现了持续的无症状假鼻疽携带者。为了更好地理解这一独特情况背后的机制，我们对相隔139个月分离的两个菌株进行了全基因组分析。在此期间，假腮腺假单胞菌经历了几次适应性变化。在23个点突变中，78%是非同义突变，43%被预测为有害于基因功能，显示出强烈的正选择倾向。值得注意的是，一个无义突变使普遍的应激反应西格玛因子rpos失活，具有多效性。基因组经历了大幅减少，2号染色体上的4个缺失导致221个基因的丢失。缺失的基因包括与次生代谢、环境生存和致病相关的基因。在14个INDELs中，11个发生在编码区，9个导致移码突变，极大地影响了预测的基因产物。不成比例地，四个吲哚影响内毒素的生物合成和修饰。最后，我们在wcbR内的两个P314分离物中都发现了移码突变，wcbR是衣壳多糖I基因座的重要组成部分，这表明在感染早期毒力减弱。我们的研究展示了一个独特的临床病例，该病例将高后果感染剂与长期共生感染进行了对比，并提供了对人类宿主内细菌进化的进一步见解。一些细菌病原体会造成长期感染，这些感染很难或不可能用目前的治疗方法根除。基因组测序技术的快速发展为了解细菌在人类宿主内的持久性提供了强大的工具。假鼻疽伯克霍尔德氏菌被认为是一种高致病性细菌，因为感染通常是致命的。在这里，我们记录了在一个独特的人类感染持续慢性携带者的病例中假腮腺炎杆菌在宿主内的进化。相隔139个月(11.5年)获得的分离株的基因组比较显示，在人类宿主内有强烈的适应信号，包括毒力和免疫原性因子的失活，以及参与环境生存的途径的缺失。在139个月的分离株中，两个全球调控基因发生了突变，表明广泛的调控变化有利于细菌的持久性。我们的研究为假鼻疽杆菌的发病机制提供了见解，更广泛地说，确定了所有细菌病原体慢性持续存在的平行进化机制。
Burkholderia pseudomallei causes the potentially fatal disease melioidosis. It is generally accepted that B. pseudomallei is a noncommensal bacterium and that any culture-positive clinical specimen denotes disease requiring treatment. Over a 23-year study of melioidosis cases in Darwin, Australia, just one patient from 707 survivors has developed persistent asymptomatic B. pseudomallei carriage. To better understand the mechanisms behind this unique scenario, we performed whole-genome analysis of two strains isolated 139 months apart. During this period, B. pseudomallei underwent several adaptive changes. Of 23 point mutations, 78% were nonsynonymous and 43% were predicted to be deleterious to gene function, demonstrating a strong propensity for positive selection. Notably, a nonsense mutation inactivated the universal stress response sigma factor RpoS, with pleiotropic implications. The genome underwent substantial reduction, with four deletions in chromosome 2 resulting in the loss of 221 genes. The deleted loci included genes involved in secondary metabolism, environmental survival, and pathogenesis. Of 14 indels, 11 occurred in coding regions and 9 resulted in frameshift mutations that dramatically affected predicted gene products. Disproportionately, four indels affected lipopolysaccharide biosynthesis and modification. Finally, we identified a frameshift mutation in both P314 isolates within wcbR, an important component of the capsular polysaccharide I locus, suggesting virulence attenuation early in infection. Our study illustrates a unique clinical case that contrasts a high-consequence infectious agent with a long-term commensal infection and provides further insights into bacterial evolution within the human host. Some bacterial pathogens establish long-term infections that are difficult or impossible to eradicate with current treatments. Rapid advances in genome sequencing technologies provide a powerful tool for understanding bacterial persistence within the human host. Burkholderia pseudomallei is considered a highly pathogenic bacterium because infection is commonly fatal. Here, we document within-host evolution of B. pseudomallei in a unique case of human infection with ongoing chronic carriage. Genomic comparison of isolates obtained 139 months (11.5 years) apart showed a strong signal of adaptation within the human host, including inactivation of virulence and immunogenic factors, and deletion of pathways involved in environmental survival. Two global regulatory genes were mutated in the 139-month isolate, indicating extensive regulatory changes favoring bacterial persistence. Our study provides insights into B. pseudomallei pathogenesis and, more broadly, identifies parallel evolutionary mechanisms that underlie chronic persistence of all bacterial pathogens.