Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis.
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5858775?pdf=render |
| _version_ | 1818457222305284096 |
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| author | Vasudevan Bakthavatchalu Katherine J Wert Yan Feng Anthony Mannion Zhongming Ge Alexis Garcia Kathleen E Scott Tyler J Caron Carolyn M Madden Johanne T Jacobsen Gabriel Victora Rudolf Jaenisch James G Fox |
| author_facet | Vasudevan Bakthavatchalu Katherine J Wert Yan Feng Anthony Mannion Zhongming Ge Alexis Garcia Kathleen E Scott Tyler J Caron Carolyn M Madden Johanne T Jacobsen Gabriel Victora Rudolf Jaenisch James G Fox |
| author_sort | Vasudevan Bakthavatchalu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T22:39:08Z |
| format | Article |
| id | doaj.art-b69d9562975649f5956ce47966a81b10 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T22:39:08Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b69d9562975649f5956ce47966a81b102022-12-21T22:45:02ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01133e019444310.1371/journal.pone.0194443Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis.Vasudevan BakthavatchaluKatherine J WertYan FengAnthony MannionZhongming GeAlexis GarciaKathleen E ScottTyler J CaronCarolyn M MaddenJohanne T JacobsenGabriel VictoraRudolf JaenischJames G FoxImmune-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.http://europepmc.org/articles/PMC5858775?pdf=render |
| spellingShingle | Vasudevan Bakthavatchalu Katherine J Wert Yan Feng Anthony Mannion Zhongming Ge Alexis Garcia Kathleen E Scott Tyler J Caron Carolyn M Madden Johanne T Jacobsen Gabriel Victora Rudolf Jaenisch James G Fox Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis. PLoS ONE |
| title | Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis. |
| title_full | Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis. |
| title_fullStr | Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis. |
| title_full_unstemmed | Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis. |
| title_short | Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis. |
| title_sort | cytotoxic escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis |
| url | http://europepmc.org/articles/PMC5858775?pdf=render |
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