3Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) cause significant morbidity and mortality worldwide (18,60,63). Though these E. coli pathotypes are genetically related, many features of their epidemiology, their pathogenesis, and the niches they occupy within the human host are unique. EPEC causes profuse watery diarrhea, primarily in children under the age of 2 years, and mostly affects individuals residing in developing countries. In contrast, adults and children infected by EHEC bacteria can suffer from either bloody or nonbloody diarrhea, and in a small percentage of cases a life-threatening complication known as hemolytic uremic syndrome (HUS) occurs. Many patients with HUS experience long-term renal damage, and they often require dialysis or kidney transplantation. EHEC produces Shiga toxins (Stx), which can cause damage to renal endothelial cells, resulting in HUS, while EPEC bacteria do not possess stx (72). EHEC disease appears in primarily industrialized nations yet causes fewer disease outbreaks in developing countries. This observation has been anecdotally attributed to immunological cross-protection from the related EPEC bacteria prevalent in the less developed regions of the world.There are two additional important differences that distinguish these two E. coli pathotypes. Approximately 10 8 to 10 10 EPEC bacteria are necessary to cause infection in adult human volunteers (6, 27), while the infectious dose for EHEC is far less, estimated to be less than 100 CFU (49). Intriguingly, EPEC infects the small intestine; EHEC infects the large bowel, inflicting bloody diarrhea resulting from damage to the colon. Variants of the outer membrane protein intimin, expressed by both pathotypes, have been implicated as contributors to tissue tropism (103), but whether intimin is the initial adhesin and, secondly, whether other factors contribute to the ability of EPEC to recognize the small bowel and of EHEC to colonize the large bowel are not clearly understood. AE. EPEC and EHEC share genetic and phenotypic similarities, most notably the locus of enterocyte effacement (LEE) pathogenicity island (PAI), encoding a type III secretion system (TTSS), and the ability to form attaching and effacing (AE) intestinal lesions, intimate attachment to the host cell, and formation of "pedestals" cupping individual bacteria (86); for recent reviews, see references 12, 60, and 95. The LEE PAI is essential for disease for both EPEC and EHEC bacteria (27,31,105). The EPEC LEE expressed from a multicopy plasmid transformed into a K-12 laboratory strain of E. coli was necessary and sufficient to form the AE phenotype on human epithelial cells in culture (80). In contrast, the EHEC LEE alone was not sufficient to confer the AE phenotype when expressed in a laboratory strain of E. coli (33), suggesting that factors and/or regulatory proteins necessary for this phenotype exist outside the EHEC LEE. Indeed, TccP (Tir-cytoskeletoncoupling protein [also called EspFu], a protein with 24% amino acid identit...