Shiga toxin-producing Escherichia coli (STEC), also called Enterohemorragic E. coli (EHEC) and vertotoxigenic E. coli (VTEC) are pathogenic bacteria that cause diarrhea, hemorrhagic colitis, hemolytic uremic syndrome (HUS), kidney failure and death in humans. Cattle are the primary reservoir for many STEC serotypes and have been implicated in most disease outbreaks through contamination of food products or the environment. Many STEC serotypes are capable of causing disease in humans, including, serotypes O157, O26, O103, O111, among others.
STEC organisms colonize the large intestine of cattle and humans by a unique mechanism in which a number of virulence determinants are delivered to host cells via a type III secretion system (TTSS), 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 STEC to the intestinal cell surface and triggers actin cytoskeletal rearrangements beneath adherent STEC that results in pedestal formation. EspA, EspB, Tir and Intimin are each essential for the successful colonization of the intestine by STEC.
Although STEC 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 STEC serotypes is responsible for about 50,000 cases of STEC infection in humans annually in the United States and Canada that result in approximately 500 deaths. In 1994, the economic cost associated with STEC infection in humans was estimated to be over 5 billion dollars.
Healthy ruminants including, but not limited to, cattle, dairy cows and sheep, could be infected with STEC serotypes. In fact, USDA reports indicate that up to 50% of cattle are carriers of STEC at some time during their lifetime and, therefore, shed STEC in their feces.
Because of the bulk processing of slaughtered cattle and the low number of STEC (10-100) necessary to infect a human, STEC colonization of healthy cattle remains a serious health problem. To address this problem, research has focused on improved methods for detecting and subsequently killing STEC at slaughter, altering the diet of cattle to reduce the number of intestinal STEC and immunizing animals to prevent STEC colonization (Zacek D. Animal Health and Veterinary Vaccines, Alberta Research Counsel, Edmonton, Canada, 1997). Recently, the recombinant production and use of STEC 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.
Babiuk et al., Microbial Pathogen. (2008) 45:7-11 describes subcutaneous and intranasal immunization of a mouse model using type III secreted proteins (TTSPs) from STEC serotype 0157:H7. U.S. Pat. No. 7,300,659 describes the use of cell culture supernatants containing STEC antigens for reducing colonization of STEC. Potter et al., Vaccine (2004) 22:362-369 reports decreased shedding of STEC serotype O157:H7 by cattle following vaccination with TTSPs. Asper et al., Vaccine (2007) 25:8262-8269 examined the cross-reactivity of TTSPs of serotypes O26:H11, O103:H2, O111:NM and O157:H7 and vaccinated cattle with TTSPs produced from each of these serotypes. The authors found the animals responded well with antibodies to TTSPs of the homologous serotype but observed limited cross-reactivity against the other serotypes. No cross-reactivity was observed against Tir and EspA of serotype O157:H7.
Despite the above, there remains a need for new compositions and methods for treating and preventing STEC disease, as well as for reducing STEC colonization of mammals in order to reduce the incidence of health problems associated with STEC-contaminated meat and water.
USPTO Backgrounds
USPTO Backgrounds