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

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere0194443
JournalPloS one
Volume13
Issue number3
DOIs
StatePublished - Mar 2018
Externally publishedYes

Fingerprint

meningitis
Meningitis
Escherichia coli
Polyketide Synthases
polyketide synthases
mice
lesions (animal)
Assays
morbidity
Clustered Regularly Interspaced Short Palindromic Repeats
Genes
Escherichia coli Meningitis
Genomic Islands
Gene therapy
Suppurative Otitis Media
genomic islands
Morbidity
colibactin
otitis media
Escherichia coli Infections

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis. / Bakthavatchalu, Vasudevan; Wert, Katherine J.; Feng, Yan; Mannion, Anthony; Ge, Zhongming; Garcia, Alexis; Scott, Kathleen E.; Caron, Tyler J.; Madden, Carolyn M.; Jacobsen, Johanne T.; Victora, Gabriel; Jaenisch, Rudolf; Fox, James G.

In: PloS one, Vol. 13, No. 3, e0194443, 03.2018.

Research output: Contribution to journalArticle

Bakthavatchalu, V, Wert, KJ, Feng, Y, Mannion, A, Ge, Z, Garcia, A, Scott, KE, Caron, TJ, Madden, CM, Jacobsen, JT, Victora, G, Jaenisch, R & Fox, JG 2018, 'Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis', PloS one, vol. 13, no. 3, e0194443. https://doi.org/10.1371/journal.pone.0194443
Bakthavatchalu, Vasudevan ; Wert, Katherine J. ; Feng, Yan ; Mannion, Anthony ; Ge, Zhongming ; Garcia, Alexis ; Scott, Kathleen E. ; Caron, Tyler J. ; Madden, Carolyn M. ; Jacobsen, Johanne T. ; Victora, Gabriel ; Jaenisch, Rudolf ; Fox, James G. / Cytotoxic Escherichia coli strains encoding colibactin isolated from immunocompromised mice with urosepsis and meningitis. In: PloS one. 2018 ; Vol. 13, No. 3.
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abstract = "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.",
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AU - Ge, Zhongming

AU - Garcia, Alexis

AU - Scott, Kathleen E.

AU - Caron, Tyler J.

AU - Madden, Carolyn M.

AU - Jacobsen, Johanne T.

AU - Victora, Gabriel

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