Molecular and evolutionary bases of within-patient genotypic and phenotypic diversity in Escherichia coli extraintestinal infections.
Molecular and evolutionary bases of within-patient genotypic and phenotypic diversity in Escherichia coli extraintestinal infections.
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DOI：
10.1371/journal.ppat.1001125
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发表时间：
2010-09-30
期刊：
影响因子：
6.7
通讯作者：
Denamur E
中科院分区：
文献类型：
--
作者：
Levert M;Zamfir O;Clermont O;Bouvet O;Lespinats S;Hipeaux MC;Branger C;Picard B;Saint-Ruf C;Norel F;Balliau T;Zivy M;Le Nagard H;Cruveiller S;Chane-Woon-Ming B;Nilsson S;Gudelj I;Phan K;Ferenci T;Tenaillon O;Denamur E
虽然由病毒、细菌、真菌和寄生虫的组合引起的多微生物感染正以越来越高的频率被认识到，但对细菌感染中种内多样性的发生以及这种多样性的分子和进化基础知之甚少。我们采用多种方法研究了19例深部和闭合性内脏感染患者的226株大肠埃希菌的基因组和表型多样性。我们观察了11例患者同一部位分离株的基因组变异。这种多样性有两种类型，因为患者感染了几种不同的E。大肠杆菌克隆（4例患者）或表现出微异质性的单个克隆的成员（11例患者）; 4例患者中存在两种类型的多样性。一个令人惊讶的广泛的抗生素耐药性，外膜渗透性，生长速度，抗应激性，红色干燥和粗糙的形态特征和毒力特性的连续存在于8的11例患者的单克隆分离株中，显示基因组微异质性。许多克隆内观察到的表型差异影响自我保护和营养能力（SPANC）之间的权衡。我们在3例患者中发现，这种表型变异与共存分离株中不同水平的RpoS相关。基因组突变分析和全球蛋白质组比较，从病人的分离株中发现了一个星状关系的变化之间的克隆分歧的分离株。一个数学模型表明，具有不同RpoS水平的多种基因型可以共存，作为SPANC权衡的结果。在涉及由一个单一的克隆感染的情况下，我们提出了几条线的证据表明在感染过程中的多样化，而不是由多个分离株表现出微观异质性的感染。我们的研究结果表明，细菌在感染过程中受到权衡，所观察到的多样性类似于实验进化研究中获得的结果。无论导致多样性的机制是什么，我们的研究结果都具有强烈的医学意义，即在决定抗生素治疗之前需要进行更广泛的分离试验。我们调查了感染是否是病原体物种内多样性的一个网站。我们的研究结果表明，确实有广泛的多样性，在人类肠外感染大肠杆菌。这种多样性有两种类型，并不相互排斥，因为我们发现患者感染了几种不同的E。coli克隆或表现出微异质性的单个克隆的成员。高度的表型多样性，包括抗生素抗性，表明在感染期间没有统一的选择压力导致单个更适合的克隆。我们讨论了一个可能的机制和数学模型，解释这些意想不到的结果。我们的数据表明，在感染过程中的多样性的演变和在体外实验进化的情况下，宿主免疫选择压力可能有许多相似之处。无论导致多样性的机制是什么，我们的研究结果都具有强烈的医学意义，即在决定抗生素治疗之前需要进行更广泛的分离试验。
Although polymicrobial infections, caused by combinations of viruses, bacteria, fungi and parasites, are being recognised with increasing frequency, little is known about the occurrence of within-species diversity in bacterial infections and the molecular and evolutionary bases of this diversity. We used multiple approaches to study the genomic and phenotypic diversity among 226 Escherichia coli isolates from deep and closed visceral infections occurring in 19 patients. We observed genomic variability among isolates from the same site within 11 patients. This diversity was of two types, as patients were infected either by several distinct E. coli clones (4 patients) or by members of a single clone that exhibit micro-heterogeneity (11 patients); both types of diversity were present in 4 patients. A surprisingly wide continuum of antibiotic resistance, outer membrane permeability, growth rate, stress resistance, red dry and rough morphotype characteristics and virulence properties were present within the isolates of single clones in 8 of the 11 patients showing genomic micro-heterogeneity. Many of the observed phenotypic differences within clones affected the trade-off between self-preservation and nutritional competence (SPANC). We showed in 3 patients that this phenotypic variability was associated with distinct levels of RpoS in co-existing isolates. Genome mutational analysis and global proteomic comparisons in isolates from a patient revealed a star-like relationship of changes amongst clonally diverging isolates. A mathematical model demonstrated that multiple genotypes with distinct RpoS levels can co-exist as a result of the SPANC trade-off. In the cases involving infection by a single clone, we present several lines of evidence to suggest diversification during the infectious process rather than an infection by multiple isolates exhibiting a micro-heterogeneity. Our results suggest that bacteria are subject to trade-offs during an infectious process and that the observed diversity resembled results obtained in experimental evolution studies. Whatever the mechanisms leading to diversity, our results have strong medical implications in terms of the need for more extensive isolate testing before deciding on antibiotic therapies. We investigated whether an infection is a site of pathogen within-species diversity. Our results indicate that there is indeed extensive diversity during human extraintestinal infections by Escherichia coli. This diversity was of two types, not mutually exclusive, as we found that patients were infected either by several distinct E. coli clones or by members of a single clone that exhibit micro-heterogeneity. The high degree of phenotypic diversity, including antibiotic resistance, suggests that there is no uniform selection pressure leading to a single fitter clone during an infection. We discuss a possible mechanism and a mathematical model that explains these unexpected results. Our data suggest that the evolution of diversity in the course of an infection and in in vitro experimental evolution in the absence of host immune selective pressure may have many parallels. Whatever the mechanisms leading to diversity, our results have strong medical implications in terms of the need for more extensive isolate testing before deciding on antibiotic therapies.
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