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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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 languageAmerican English
Article numbere00558-17
JournalInfection and Immunity
Volume85
Issue number11
DOIs
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© 2017 American Society for Microbiology.

Keywords

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

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