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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  W   sh   /W   sh   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 .

Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis