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.

免疫受损的小鼠模型可以在进行临床试验之前测试人细胞移植的临床前功效和基因治疗策略。然而，对W ^sh / W ^sh小鼠品系的CRISPR / Cas9基因编辑以创建缺乏Rag2和Il2rγ功能的免疫受损模型导致了意外的发病率和死亡率。这需要进行调查以确定与爆发有关的原因和诱发因素。在15只垂死的小鼠上进行了死后检查。在这些小鼠中观察到的主要病变包括泌尿生殖道感染，化脓性中耳炎，肺炎，心肌炎和脑膜脑脊髓炎。作为大肠杆菌最近从实验室小鼠中分离出了带有聚酮化合物合酶（pks）基因岛的菌株，并对泌尿生殖道，心脏和中耳的组织切片进行了E检验。大肠杆菌特异性PNA-FISH测定法揭示的离散的菌落É。与病灶相关的大肠埃希菌。微生物检验和的16S rRNA测序证实ê。大肠埃希菌在感染小鼠中引起的感染和败血病。通过clb基因分析和大肠埃希菌对pks + E的毒性分析进一步表征。大肠杆菌揭示大肠菌素相关的细胞毒性。使用胚胎移植重新转基因小鼠，产生了没有pks + E的肠道菌群的小鼠。大肠杆菌。重要的是，这些屏障维持的重做小鼠已经产生了多个垫料，而没有不利的健康影响。该报告是第一个描述与pks + E相关的急性发病率和死亡率的报告。大肠杆菌尿路败血症和脑膜炎的亮点在免疫缺陷小鼠，并监测和colibactin产生的排斥的重要性PKS + E。大肠杆菌。