Enterohemorragic Escherichia coli (EHEC), also called Shiga toxin E. coli (STEC) and vertotoxigenic E. coli (VTEC) are pathogenic bacteria that cause diarrhea, hemorrhagic colitis, hemolytic uremic syndrome, kidney failure and death in humans. While many Shiga-like toxin producing EHEC strains are capable of causing disease in humans, those of serotype O157:H7 cause the majority of human illness. This organism is able to colonize the large intestine of humans by a unique mechanism in which a number of virulence determinants are delivered to host cells via a type III secretion system, including the translocated Intimin receptor, Tir (DeVinney et al., Infect. Immun. (1999) 67:2389). In particular, these pathogens secrete virulence determinants EspA, EspB and EspD that enable delivery of Tir into intestinal cell membranes. Tir is integrated into the host cell membrane where it serves as the receptor for a bacterial outer membrane protein, Intimin. Tir-Intimin binding attaches EHEC to the intestinal cell surface and triggers actin cytoskeletal rearrangements beneath adherent EHEC that results in pedestal formation. EspA, EspB, Tir and Intimin are each essential for the successful colonization of the intestine by EHEC.
Although EHEC colonize the intestine of ruminants and other mammals, they generally do not cause overt disease in these animals. However, contamination of meat and water by the EHEC serotype O157:H7 (hereinafter, “EHEC O157:H7”) is responsible for about 50,000 cases of EHEC O157:H7 infection in humans annually in the United States and Canada that result in approximately 500 deaths. In 1994, the economic cost associated with EHEC O157:H7 infection in humans was estimated to be over 5 billion dollars annually.
The first documented EHEC O157:H7 outbreak traced to contaminated meat occurred in 1982. Subsequently, it was demonstrated that healthy ruminants including, but not limited to, cattle, dairy cows and sheep, could be infected with EHEC O157:H7. In fact, USDA reports indicate that up to 50% of cattle are carriers of EHEC O157:H7 at some time during their lifetime and, therefore, shed EHEC O157:H7 in their feces.
Because of the bulk processing of slaughtered cattle and the low number of EHEC O157:H7(10-100) necessary to infect a human, EHEC O157:H7 colonization of healthy cattle remains a serious health problem. To address this problem, research has focused on improved methods for detecting and subsequently killing EHEC O157:H7 at slaughter, altering the diet of cattle to reduce the number of intestinal EHEC O157:H7 and immunizing animals to prevent EHEC O157:H7 colonization (Zacek D. Animal Health and Veterinary Vaccines, Alberta Research Counsel, Edmonton, Canada, 1997). Recently, the recombinant production and use of EHEC O157:H7 proteins including recombinant EspA (International Publication No. WO 97/40063), recombinant TIR (International Publication No. WO 99/24576), recombinant EspB and recombinant Initimin (Li et al., Infec. Immun. (2000) 68:5090-5095) have been described. However, production and purification of recombinant proteins in amounts sufficient for use as antigens is both difficult and expensive. At the present time, there is no effective method for blocking EHEC O157:H7 colonization of cattle and other mammals and, thereby, for reducing shedding of EHEC into the environment.
Therefore, there is a need for new compositions and methods for treating and preventing EHEC disease, as well as for reducing EHEC colonization of mammals in order to reduce the incidence of health problems associated with EHEC-contaminated meat and water.
USPTO Backgrounds
USPTO Backgrounds