Molecular and Evolutionary Bases of Within-Patient Genotypic and Phenotypic Diversity in Escherichia coli Extraintestinal Infections

PLoS Pathogens

Bertrand Picard¹  Marie Claire Hipeaux¹  Michel Zivy²  Hervé Le Nagard²  Ivana Gudelj³  Katherine Phan³  Françoise Norel⁴  Claude Saint-Ruf⁵  Oana Zamfir⁵  Catherine Branger⁵  Odile Bouvet⁵  Erick Denamur⁵  Maxime Levert⁵  Sylvain Lespinats⁵  Olivier Clermont⁵  Stéphane Cruvellier⁶  Susanna Nilsson⁷  Béatrice Chane-Woon-Ming⁷  Thomas Ferenci⁸  Olivier Tenaillon⁸  Thierry Balliau⁹ 

[1] Assistance Publique - Hôpitaux de Paris, Hôpital Louis Mourier, Laboratoire de Microbiologie, Colombes, France;CNRS UMR 0320/UMR8120 Génétique Végétale, Plate-Forme de Protéomique PAPPSO, Gif-sur-Yvette, France;Department of Mathematics, Imperial College, London, United Kingdom;INSERM U1001 and Université Paris 5 René Descartes, Faculté de Médecine, Paris, France;INSERM U722 and Université Paris 7 Denis Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, France;INSERM U738 and Université Paris 7 Denis Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, France;Laboratoire de Génomique Comparative, CNRS UMR8030, Institut de Génomique, CEA, Genoscope, Evry, France;School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia;Unité de Génétique Moléculaire and CNRS URA2172, Institut Pasteur, Paris, France

关键词: Antibiotic resistance;    Cloning;    Escherichia coli infections;    Outer membrane proteins;    Human genetics;    Evolutionary immunology;    Antibiotics;    Point mutation;   

DOI  :  10.1371/journal.ppat.1001125

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY