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.
Highlights
Enterohemorrhagic Escherichia coli (EHEC) is an emerging zoonotic pathogen that causes acute human gastroenteritis and hemorrhagic colitis (Kaper et al, 2004)
Studies on EHEC pathogenesis are hampered by a lack of suitable animal models that can fully recapitulate the natural disease in humans
In our study, the xenografts were essentially germ-free and all of the pathogenic effects on the tissue were directly related to EHEC, because microflora components were not involved. These results show that the presence of microflora is not essential for EHEC virulence, a conclusion that is supported by a previous study using human in vitro organ culture (IVOC) (Chong et al, 2007)
Summary
Enterohemorrhagic Escherichia coli (EHEC) is an emerging zoonotic pathogen that causes acute human gastroenteritis and hemorrhagic colitis (Kaper et al, 2004). EHEC causes disease in newborn calves and asymptomatically colonizes the gut mucosa of adult bovines, constituting the main reservoir for food and environmental contamination (Chase-Topping et al, 2008). EHEC elicits a histopathology termed attaching and effacing (AE) lesions. This includes intimate attachment of the bacteria to the apical surface of the epithelial cells, disruption of the brush border microvillus, and accumulation of polymerized actin beneath the attached bacteria forming structures termed ‘actin. Epithelial adhesion and colonization of the bovine terminal rectal mucosa, which is currently considered the prime site for carriage and shedding, was unaffected by the absence of Stx (Sheng et al, 2006). In an infant rabbit model, Stx increased the severity and duration of EHEC-induced diarrhea and purified Stx was able to induce inflammation and diarrhea (Ritchie et al, 2003)
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