Enterohemorrhagic Escherichia coli induce attaching and effacing lesions and hemorrhagic colitis in human and bovine intestinal xenograft models

Abstract

SUMMARYEnterohemorrhagic Escherichia coli (EHEC) O157:H7 is an important cause of diarrhea, hemorrhagic colitis and hemolytic uremic syndrome in humans worldwide. The two major virulence determinants of EHEC are the Shiga toxins (Stx) and the type III secretion system (T3SS), including the injected effectors. Lack of a good model system hinders the study of EHEC virulence. Here, we investigated whether bovine and human intestinal xenografts in SCID mice can be useful for studying EHEC and host tissue interactions. Fully developed, germ-free human and bovine small intestine and colon were established by subcutaneous transplantation of human and bovine fetal gut into SCID mice. Xenografts were allowed to develop for 3–4 months and thereafter were infected by direct intraluminal inoculation of Stx-negative derivatives of EHEC O157:H7, strain EDL933. The small intestine and colon xenografts closely mimicked the respective native tissues. Upon infection, EHEC induced formation of typical attaching and effacing lesions and tissue damage that resembled hemorrhagic colitis in colon xenografts. By contrast, xenografts infected with an EHEC mutant deficient in T3SS remained undamaged. Furthermore, EHEC did not attach to or damage the epithelium of small intestinal tissue, and these xenografts remained intact. EHEC damaged the colon in a T3SS-dependent manner, and this model is therefore useful for studying the molecular details of EHEC interactions with live human and bovine intestinal tissue. Furthermore, we demonstrate that Stx and gut microflora are not essential for EHEC virulence in the human gut.

Mecanismos de virulencia de Escherichia coli enteropatógena

“…Los mecanismos fisiopatológicos que originan el cuadro diarreico se relacionan principalmente con la alteración de la célula intestinal debido a la lesión de adhesión y borrado (A/E: attaching/effacing) y a la formación de pedestales 15,16 .…”

In Vitro and In Vivo Model Systems for Studying Enteropathogenic Escherichia coli Infections

“…Germ-free mice have been used to study toxin suppression and production of other virulence factors by EHEC as well as the use of probiotics for protection against colonization and EHEC-mediated disease (Takahashi et al 2004;Eaton et al 2008Eaton et al , 2011. Alternatively, human xenografts of the small and large intestine in severe combined immunodeficiency mice have recently been proposed as a model to evaluate T3S effector function in native tissue and to investigate tissue tropism (Golan et al 2011). EHEC is able to specifically interact with human colonic xenografts, inducing A/E lesions and tissue damage dependent on a functional T3SS (Golan et al 2011).…”

“…Alternatively, human xenografts of the small and large intestine in severe combined immunodeficiency mice have recently been proposed as a model to evaluate T3S effector function in native tissue and to investigate tissue tropism (Golan et al 2011). EHEC is able to specifically interact with human colonic xenografts, inducing A/E lesions and tissue damage dependent on a functional T3SS (Golan et al 2011). This type of model has also been used to show that H7 flagellin is a major factor involved in increases of proinflammatory chemokines in response to EHEC infection (Miyamoto et al 2006).…”

Retinoid Levels Influence Enterohemorrhagic Escherichia coli Infection and Shiga Toxin 2 Susceptibility in Mice

“…Therefore, EHEC-associated pathologies, with high morbidity and mortality rates, presume a serious public health problem (2,3). EHEC has the capacity to intimately attach to and efface intestinal epithelial cells, a pathology called the attaching-and-effacing (A/E) lesion (4,5). Most of the genes involved in A/E lesion formation are carried on the locus of enterocyte effacement pathogenicity island (6).…”