FIG 9.

Diarrheagenic Afa/Dr DAEC strain C1845 promotes epithelial-mesenchymal transition (EMT)-like behavior, cell extrusion, and pks-dependent damage in human intestinal cells. The drawing on the left summarizes the observed EMT-related cellular events. An F1845-triggered hDAF-, MAPKs-, PI3K-, and HIF-1α-dependent production of VEGF develops in colonic-like T84 cells (1 and 2). An F1845-triggered hDAF-, MAPKs-, PI3K-, and HIF-1α-dependent EMT-like behavior develops, characterized by the typical changes in expression of mesenchymal markers, such as the upregulation of fibronectin, the downregulation of CK18, and the disappearance of AJ-associated E-cadherin (1 and 3). Finally, depolarized intestinal cells lose the lateral cell-to-cell and basal contacts and become detached from the cell monolayer. (A) Low-magnification transmission electron micrographs show the dedifferentiation of Caco-2/TC7 cells infected with the diarrhea-associated strain C1845, characterized by a disorganization of the apical domain and by the appearance of nucleus fragmentation and loss of nucleus dense electron material, indicating cell death (left micrograph). The boxed area indicates a cell with a funnel form engaging in shedding from the cell monolayer as the result of the wide opening of the lateral cell-to-cell junctional domain and detachment at the basal domain. The micrograph on the right shows a high magnification of the cell engaging in detachment and containing a high number of vesicles in the cytoplasm. (B) Low- and high-magnification micrographs show the morphological changes in Giemsa-stained C1845-infected undifferentiated Caco-2/TC7, cells characterized by an enlargement of the cell body and nucleus. Low-magnification micrographs show the increase of the phosphorylation of nuclear H2AX, the most sensitive marker of DNA damage. (Courtesy of J. P. Nougayrede and E. Oswald, reproduced with permission.)