Type three secretion systemdependent microvascular thrombosis and ischemic enteritis in human gut xenografts infected with enteropathogenic Escherichia coli

Einat Nissim-Eliraz, Eilam Nir, Irit Shoval, Noga Marsiano, Israel Nissan, Hadar Shemesh, Nandor Nagy, Allan M. Goldstein, Michael Gutnick, Ilan Rosenshine, Simcha Yagel, Nahum Y. Shpigela

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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 attaching and effacing (AE) lesions 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.

Original languageEnglish
Article numbere00558-17
JournalInfection and Immunity
Issue number11
StatePublished - Nov 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 American Society for Microbiology.


NIH grant R21 AI107587 to Nahum Y. Shpigel and Ilan Rosenshine supported this work. Nahum Y. Shpigel, Allan M. Goldstein, and Michael Gutnick were supported by BSF grant 2015157. The work leading to the results presented here has received funding from the European Union Seventh Framework Programme (FP7/2012-2017) under grant agreement no. 305564 as a partner of the SysmedIBD Research Consortium (to Werner Muller, University of Manchester, Manchester, United Kingdom).

FundersFunder number
University of Manchester, Manchester
National Institute of Allergy and Infectious DiseasesR21AI107587
United States-Israel Binational Science Foundation2015157
Seventh Framework Programme305564


    • EPEC
    • Human gut xenograft
    • Mouse model
    • T3SS
    • Thrombotic microangiopathy


    Dive into the research topics of 'Type three secretion systemdependent microvascular thrombosis and ischemic enteritis in human gut xenografts infected with enteropathogenic Escherichia coli'. Together they form a unique fingerprint.

    Cite this