1. The genotoxin colibactin is a determinant of virulence in Escherichia coli K1 experimental neonatal systemic infection
- Author
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Peter W. Taylor, Richard A. Stabler, Emilie Cloup, Alex J. McCarthy, Eric Oswald, Patricia Martin, School of Pharmacy, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), London School of Hygiene and Tropical Medicine (LSHTM), Centre de Physiopathologie de Toulouse-Purpan (INSERM U563 - CNRS UMR1037), CHU Toulouse [Toulouse]-Institut Claudius Regaud-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de lutte contre le cancer (CLCC)-Centre National de la Recherche Scientifique (CNRS), Service Bactériologie-Hygiène, Centre Hospitalier Universitaire de Toulouse, Medical Research Council [MR/K018396/1], Agence Nationale de la Recherche [ANR-13-BSV1-0028-01], Aninfimip platform, an EquipEx (Equipement d'Excellence) platform - French government through the Investments for the Future program [ANR-11-EQPX-0003], National Institute for Health Research University College London Hospitals Biomedical Research Centre, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut Claudius Regaud-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de lutte contre le cancer (CLCC)-Centre National de la Recherche Scientifique (CNRS), Service Bactériologie et hygiène [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and ProdInra, Migration
- Subjects
Genome instability ,Genomic Islands ,[SDV]Life Sciences [q-bio] ,Immunology ,Molecular Sequence Data ,Virulence ,Biology ,medicine.disease_cause ,Microbiology ,Polymerase Chain Reaction ,medicine ,Escherichia coli ,Animals ,Rats, Wistar ,Gene ,Escherichia coli Infections ,Genetics ,Gastrointestinal tract ,Mutation ,Base Sequence ,Pathogenicity island ,Molecular Pathogenesis ,Immunohistochemistry ,3. Good health ,Rats ,[SDV] Life Sciences [q-bio] ,Complementation ,Disease Models, Animal ,Infectious Diseases ,Animals, Newborn ,Polyketides ,Parasitology ,Peptides - Abstract
Escherichia coli strains expressing the K1 capsule are a major cause of sepsis and meningitis in human neonates. The development of these diseases is dependent on the expression of a range of virulence factors, many of which remain uncharacterized. Here, we show that all but 1 of 34 E. coli K1 neonatal isolates carried clbA and clbP , genes contained within the pks pathogenicity island and required for the synthesis of colibactin, a polyketide-peptide genotoxin that causes genomic instability in eukaryotic cells by induction of double-strand breaks in DNA. Inactivation of clbA and clbP in E. coli A192PP, a virulent strain of serotype O18:K1 that colonizes the gastrointestinal tract and translocates to the blood compartment with very high frequency in experimental infection of the neonatal rat, significantly reduced the capacity of A192PP to colonize the gut, engender double-strand breaks in DNA, and cause invasive, lethal disease. Mutation of clbA , which encodes a pleiotropic enzyme also involved in siderophore synthesis, impacted virulence to a greater extent than mutation of clbP , encoding an enzyme specific to colibactin synthesis. Restoration of colibactin gene function by complementation reestablished the fully virulent phenotype. We conclude that colibactin contributes to the capacity of E. coli K1 to colonize the neonatal gastrointestinal tract and to cause invasive disease in the susceptible neonate.
- Published
- 2015
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