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Infect Immun. 2017 Aug 7. pii: IAI.00558-17. doi: 10.1128/IAI.00558-17. [Epub ahead of print]

T3SS-dependent microvascular thrombosis and ischemic enteritis in human gut xenografts infected with enteropathogenic Escherichia coli.

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The Koret School of Veterinary Medicine, The Hebrew University of Jerusalem, POB 12, Rehovot 76100, Israel.
Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Jerusalem, The Hebrew University of Jerusalem.
Department of Obstetrics and Gynecology, Hadassah University Hospital, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
The Koret School of Veterinary Medicine, The Hebrew University of Jerusalem, POB 12, Rehovot 76100, Israel


Enteropathogenic Escherichia coli (EPEC) is a leading cause of severe intestinal disease and infant mortality in developing countries. Virulence is mediated by a type three secretion system (T3SS) causing the hallmark lesions of attaching and effacing (AE) and actin-rich pedestal formation beneath the infecting bacteria on the apical surface of enterocytes. EPEC is a human-specific pathogen whose pathogenesis cannot be studied in animal models. We therefore established an EPEC infection model in human gut xenografts in SCID mice and used it to study the role of T3SS in the pathogenesis of the disease. Following EPEC O127:H6 strain E2348/69 infection, T3SS-dependent AE lesions and pedestals were demonstrated in all infected xenografts. We report here the development of T3SS-dependent intestinal thrombotic microangiopathy (iTMA) and ischemic enteritis in ∼50% of infected human gut xenografts. Using species-specific CD31 immunostaining, we showed that iTMA was limited to the larger human-mouse chimeric blood vessels which are located between the muscularis mucosa and circular muscular layer of the human gut. These blood vessels were massively invaded by bacteria which adhered to and formed pedestals on endothelial cells and aggregated with mouse neutrophils in the lumen. We conclude that endothelial infection, iTMA and ischemic enteritis might be central mechanisms underlying severe EPEC-mediated disease.

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