title: Pathoadaptive Mutations of Escherichia coli K1 in Experimental Neonatal Systemic Infection.
abstract: Although Escherichia coli K1 strains are benign commensals in adults, their acquisition at birth by the newborn may result in life-threatening systemic infections, most commonly sepsis and meningitis. Key features of these infections, including stable gastrointestinal (GI) colonization and age-dependent invasion of the bloodstream, can be replicated in the neonatal rat. We previously increased the capacity of a septicemia isolate of E. coli K1 to elicit systemic infection following colonization of the small intestine by serial passage through two-day-old (P2) rat pups. The passaged strain, A192PP (belonging to sequence type 95), induces lethal infection in all pups fed 2-6 x 106 CFU. Here we use whole-genome sequencing to identify mutations responsible for the threefold increase in lethality between the initial clinical isolate and the passaged derivative. Only four single nucleotide polymorphisms (SNPs), in genes (gloB, yjgV, tdcE) or promoters (thrA) involved in metabolic functions, were found: no changes were detected in genes encoding virulence determinants associated with the invasive potential of E. coli K1. The passaged strain differed in carbon source utilization in comparison to the clinical isolate, most notably its inability to metabolize glucose for growth. Deletion of each of the four genes from the E. coli A192PP chromosome altered the proteome, reduced the number of colonizing bacteria in the small intestine and increased the number of P2 survivors. This work indicates that changes in metabolic potential lead to increased colonization of the neonatal GI tract, increasing the potential for translocation across the GI epithelium into the systemic circulation.
authors.affiliation: University College London School of Pharmacy, London, United Kingdom.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: McCarthy
authors.affiliation: University College London School of Pharmacy, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Negus
authors.affiliation: UMR1220 Inserm, Toulouse, France.|UMR 1416 INRA, Toulouse, France.|Université de Toulouse, UPS, Institut de Recherche en Santé Digestive, Toulouse, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martin
authors.affiliation: University College London School of Pharmacy, London, United Kingdom.
authors.forename: Catarina
authors.initials: C
authors.lastname: Pechincha
authors.affiliation: UMR1220 Inserm, Toulouse, France.|UMR 1416 INRA, Toulouse, France.|Université de Toulouse, UPS, Institut de Recherche en Santé Digestive, Toulouse, France.|CHU Toulouse, Hôpital Purpan, Service de Bactériologie-Hygiène, Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Oswald
authors.affiliation: London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Stabler
authors.affiliation: University College London School of Pharmacy, London, United Kingdom.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Taylor
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000382:microbiology*; D041981:Gastrointestinal Tract / Q000382:microbiology; D016680:Genome, Bacterial; D023281:Genomics; D006801:Humans; D009154:Mutation; D010802:Phylogeny; D040901:Proteomics / Q000379:methods; D051381:Rats; D014774:Virulence / Q000235:genetics