EPEC is a major cause of neonatal diarrhea in developing countries, killing close to 1 million children each year due to dehydration, malnutrition and other complications of the disease. In North America, there have been occasional nursery school outbreaks of diarrhea attributed to EPEC. Pathogenesis of EPEC requires intimate attachment of the bacteria to cells in the host’s small intestine. The bacteria induce the formation of pedestal-like structures on the host cell surface upon which they rest.
EHEC or E. coli O157:H7 is an emerging cause of diarrhea in the developed world. In the United States, 10 000 to 20 000 cases are reported yearly. It has been found in ground beef, unpasteurized milk, bottled juices and sewage contaminated water. EHEC causes a bloody diarrhea which can lead to kidney failure especially in young children and the elderly. Pathogenesis of EHEC is similar to EPEC but EHEC also secretes a verotoxin thus causing a more serious disease.
Our lab is studying the mechanism by which these E. coli attach to host cells. Other pathogens adhere to host cells by binding pre-existing receptors, but these pathogenic E. coli have a novel mechanism of adherence – they manufacture and inject their own receptor into the host cell to which then can subsequently bind. This is accomplished through a 78-kDa bacterial protein called Tir that is injected into host cells to be further modified into a 90-kDa receptor previously described as Hp90. Through structure function analysis of Tir, we are studying its interaction with Intimin and subsequent pedestal formation.
While attached, the bacteria also have a mechanism of avoiding uptake in to the host cell. We are trying to determine which factors are necessary in preventing phagocytosis of the bacteria. In addition, we are studying other bacterial secreted proteins to determine the role that they play in the pathogenesis of diarrhea.
We are also developing other models of E. coli infection to determine if these bacterial proteins are important in vivo. One project currently underway is to investigate the effectiveness of Tir as a vaccine to prevent EHEC colonization, in collaboration with ID Biomedical Corporation.
We realize that the bacteria already have an intimate understanding of eucaryotic cell biology, exploiting many normal host cell processes to aid in the proliferation of their own kind. As we begin to understand the pathogenesis of EPEC and EHEC infections, we hope to find new therapeutic options against these diseases and thus impose new barriers for these bacteria to overcome.
One example of some of the practical applications that have been developed from our research is the E. coli 0157 cow vaccine, produced in collaboration with Bioniche Life Sciences Inc.