colibactin and Urinary-Tract-Infections

Urinary tract infections (UTIs) are among the most common outpatient infections, with a lifetime incidence of around 60% in women. We analysed urine samples from 223 patients with community-acquired UTIs and report the presence of the cleavage product released during the synthesis of colibactin, a bacterial genotoxin, in 55 of the samples examined. Uropathogenic Escherichia coli strains isolated from these patients, as well as the archetypal E. coli strain UTI89, were found to produce colibactin. In a murine model of UTI, the machinery producing colibactin was expressed during the early hours of the infection, when intracellular bacterial communities form. We observed extensive DNA damage both in umbrella and bladder progenitor cells. To the best of our knowledge this is the first report of colibactin production in UTIs in humans and its genotoxicity in bladder cells.

Topics: Aged; Animals; DNA Damage; Escherichia coli Infections; Female; Humans; Male; Mice; Mice, Inbred C3H; Mutagens; Peptides; Polyketides; Urinary Bladder; Urinary Tract Infections; Uropathogenic Escherichia coli

A functional synergy was previously demonstrated between microcin, salmochelin and colibactin islands in Escherichia coli strains from B2 phylogroup. We aimed to determine this association prevalence in uropathogenic E. coli, and whether it was predictive of the infection severity in a collection of 225 E. coli strains from urinary samples. The high prevalence of this triad, even if it wasn't correlated with infection severity, suggested that it might not be a virulence factor per se within the urinary tract, but would promote its colonization. This triad would enable the strain to dominate the rectal reservoir with a minimal genetic cost.

Topics: Bacteriocins; Enterobactin; Escherichia coli Infections; Humans; Multigene Family; Peptides; Polyketides; Urinary Tract Infections; Uropathogenic Escherichia coli; Virulence

Immune-compromised mouse models allow for testing the preclinical efficacy of human cell transplantations and gene therapy strategies before moving forward to clinical trials. However, CRISPR/Cas9 gene editing of the Wsh/Wsh mouse strain to create an immune-compromised model lacking function of Rag2 and Il2rγ led to unexpected morbidity and mortality. This warranted an investigation to ascertain the cause and predisposing factors associated with the outbreak. Postmortem examination was performed on 15 moribund mice. The main lesions observed in these mice consisted of ascending urogenital tract infections, suppurative otitis media, pneumonia, myocarditis, and meningoencephalomyelitis. As Escherichia coli strains harboring polyketide synthase (pks) genomic island were recently isolated from laboratory mice, the tissue sections from the urogenital tract, heart, and middle ear were subjected to E. coli specific PNA-FISH assay that revealed discrete colonies of E. coli associated with the lesions. Microbiological examination and 16S rRNA sequencing confirmed E. coli-induced infection and septicemia in the affected mice. Further characterization by clb gene analysis and colibactin toxicity assays of the pks+ E. coli revealed colibactin-associated cytotoxicity. Rederivation of the transgenic mice using embryo transfer produced mice with an intestinal flora devoid of pks+ E. coli. Importantly, these barrier-maintained rederived mice have produced multiple litters without adverse health effects. This report is the first to describe acute morbidity and mortality associated with pks+ E. coli urosepsis and meningitis in immunocompromised mice, and highlights the importance of monitoring and exclusion of colibactin-producing pks+ E. coli.

Topics: Animals; Escherichia coli; Immunocompromised Host; Meningitis, Bacterial; Mice; Mice, Transgenic; Peptides; Polyketides; Sepsis; Urinary Tract Infections