Investigating the role of blood group antigens in campylobacter infections

The bacterium Campylobacter jejuni is one of the most important causes of food poisoning worldwide. It can cause a spectrum of illness from mild diarrhoea to severe dysentery-like illness. Although not normally life-threatening, these infections are very common and are costly in terms of time taken off work and healthcare-associated costs. Occasionally Campylobacter disease results in very serious complications including the life-threatening neurological disease Guillain-Barre syndrome. The bacterium normally lives in the gut of wild and domesticated animals, notably chickens. Improper handling and undercooking of chicken are major sources of human infection. At present we do not have a good understanding of the factors that affect colonisation of animals or disease in humans. A better understanding of these complex processes will be necessary to design new strategies for preventing colonisation of domesticated animals, especially chickens, as well as human disease. We have shown two Campylobacter surface molecules, called FlaA and MOMP, to be involved in binding to receptors on human blood cells and intestinal cells. We propose to characterise the interaction between the bacteria and human cells that are mediated by these molecules. We also propose to determine whether these molecules are also important in colonisation of chickens. The information gained may lead to the development of agents that interfere with these interactions, and thus reduce both contamination of chicken meat, as well as reduce human disease.

Campylobacter species are the commonest reported bacterial causes of gastroenteritis in the UK and industrialized world. C. jejuni is responsible for about 90% of cases, the majority of the remainder being caused by C. coli. Campylobacter species form part of the natural gastrointestinal flora of many birds and domestic animals, but chickens are thought to constitute the largest source of human infection. In humans, Campylobacter species cause diseases that vary in severity from mild watery diarrhoea to bloody dysentery. In a small subgroup of patients, the acute phase disease is followed by serious sequelae, including Guillain-Barre syndrome and reactive arthritis. Prevention and treatment of campylobacteriosis and its consequences are hampered by a poor understanding of the detailed molecular interaction between the host and the pathogen.
Previous reports have indicated that adherence of C. jejuni to epithelial cells can be partially inhibited by fucosylated sugar components of human breast milk, which were later identified as the host blood group antigens (BgAgs) H1 and H2. Furthermore, the attachment of H2 antigen to C. jejuni could be inhibited by fucosyl-lactose contained in human milk.
Our preliminary work leading up to this application confirmed that C. jejuni specifically binds all human BgAgs. The bacterial ligands responsible for binding are the flagellin protein FlaA and the major outer membrane protein (MOMP). Unusually, MOMP appears to be O-glycosylated, and may share a common BgAg binding site with FlaA, which has already been shown to be O-glycosylated. The data also suggest that the BgAgs can inhibit bacterial adhesion and biofilm formation.
The overall aim of this proposal is to develop a better understanding of the host-pathogen interaction with the ultimate objective of developing preventative and/or modulatory agents that would block human and animal colonisation and disease. The immediate objectives of this study are to investigate the structure and function of the Campylobacter ligands that bind BgAgs and determine the role of BgAgs in Campylobacter auto-agglutination, biofilm formation, host-pathogen interaction and prevention and/or termination of C. jejuni colonisation.