Host-pathogen interactions important in the movement of Campylobacter jejuni from the broiler chicken gut to edible tissues (CampAttack)

Sustainable production of safe chicken is an international priority and it is estimated that in the next 20 years chicken production will have to quadruple to satisfy growing global demand. The key question is whether this can be done in a way that does not increase the public health threat of contaminated chicken meat and preserves chicken health and welfare. Most chicken meat consumed internationally is produced in large-scale intensive (broiler) systems and most birds in the UK (>75%) are Campylobacter-positive at retail, mainly with C. jejuni, posing a huge public health threat. Campylobacter is the most common cause of bacterial diarrhoea in the UK and despite millions of pounds of research funding it is estimated that contaminated chicken caused >500000 human campylobacteriosis cases in the UK in 2016 with around 100 deaths, mainly in elderly people. Infection is characterised by severe abdominal pain and acute (sometimes bloody) diarrhoea and costs the UK economy over £1 billion per year. In addition, Campylobacter are not only major chicken-associated human pathogens, they also compromise the health, welfare and performance of broilers.
Campylobacter contamination of chicken takes two forms. First, surface contamination of carcasses, as a result of spillage of gut contents during slaughter, can lead to cross-contamination in the kitchen. Second, and perhaps of greater importance than currently thought, is contamination within muscle and liver tissues, which increases the health risk by facilitating bacterial survival during cooking. Until recently it was believed that Campylobacter only colonised the lower gut of the chicken (the caecum). However, spread from the gut to edible tissues is associated with the ability of certain Campylobacter strains to colonise the upper intestine of the chicken, where the gut lining (mucosa) is more easily damaged. As Campylobacter comprise a diverse population in broilers, with different strains varying in their effects on gut integrity and their ability to spread to edible tissues like liver and muscle, it is important to better understand the host-pathogen interactions of different types if the bacteria are to be controlled in chickens and the public health threat reduced. In particular, it is essential to identify the key host immune responses and the bacterial genes most important in these interactions - and in colonisation of the whole gut and extra-intestinal spread. This information, which is currently not available, is essential for the development of immunity-based and other control measures.
This multidisciplinary research programme will enhance understanding of the influence of Campylobacter strain on bird gut health, host innate immune responses and spread to edible tissues and thus the public health threat. The quantitative information and modelling will be used to give direct advice to industry about Campylobacter infection biology in broiler chickens, providing an unprecedented basis for interventions to mitigate the on-going challenge of Campylobacter contamination in chicken meat. These interventions potentially include new vaccines and/or genetically more resistant chickens.

Campattack technical summary
Key tenets of sustainable chicken production are that the animals' health and welfare should be protected and that the end products should not endanger public health. Worldwide most (>75%) chickens are Campylobacter-positive at point of sale, mainly with C. jejuni, and it is estimated that 80% of human cases (~500000) in the UK are chicken-associated. Most UK chickens are grown using intensive systems (broiler production), which can compromise bird welfare and raise the Campylobacter public health threat. There is increasing evidence that edible tissues of chicken, particularly liver, are C. jejuni-positive. Our preliminary data show that infection of liver tissues is a consequence of colonisation of the upper gut with strains of C. jejuni that are inherently better able to leave this organ. Host inflammatory responses, the levels of which are C. jejuni strain-dependent, also play an important role. Building on a strong novel dataset, which has identified a suite of C. jejuni genes and host innate immune responses involved in extra-intestinal spread, our proposed studies will determine the major processes underlying this important bird and public health scenario.
We and our industrial partner Merck Animal Health will conduct in vitro experiments, using novel chicken epithelial cell lines, and infect commercial chickens (Ross 308) in in vivo experiments with wild type C. jejuni and strains with mutations in some of the genes that we have identified as being of high importance. We will also use birds inherently deficient in key immune processes. A range of host immune responses will be measured in all experiments. The identification of the most important pathogen mechanisms and host immune responses involved in the extra-intestinal spread of C. jejuni will inform breeding programmes and immunity-based controls. We will use modelling to investigate the relative importance of the underlying biological mechanisms.

This proposed research will generate new knowledge with the specific aim of enabling the broiler industry to develop better interventions for reducing the problems posed by widespread C. jejuni infection. Specifically, it is intended to provide data to inform our industry partners in developing potential new vaccines and/or chicken breeds resistant to the most damaging and dangerous C. jejuni strains. Industry relevance is underscored by the level of support and involvement - we have three major companies involved in the production chain as active partners. Alongside poultry and allied industry stakeholders, other potential beneficiaries include policymakers in agriculture and food safety, who will benefit from the availability of better control measures, and the public, who will be better protected.
Sustainable production of safe chicken is an international priority and good bird health and welfare are key components of this. It is estimated that global chicken production will have to quadruple over the next ~20 years to satisfy rising demand. However, with around 75% of chickens on sale in the UK Campylobacter-positive, mainly with C. jejuni and a well-established body of research to show that this bacterium is an important endemic chicken pathogen affecting bird health and therefore performance (particularly in rapid-growing breeds), the industry's sustainability is jeopardised.
Contaminated chicken presents two human-health threats. Surface contamination levels can be very high and this can pose a cross-contamination risk during catering. Of greater importance is contamination of deep muscle and liver tissues, reported in up to 27% and 60% of samples respectively. Many epidemiological investigations worldwide have shown that the greater public health risk is from contaminated tissues, where the bacteria are better protected from heat during cooking and under-cooked meat and liver are major infection vehicles. Campylobacter inside undercooked meat and liver will also be better protected from gastric acidity. Broiler producers need to better protect birds from Campylobacter infection but this is very difficult to achieve at present, particularly in summer, as the industry does not have the tools to do so. Of perhaps greater importance for the immediate future is to develop strategies and interventions for confining Campylobacter, principally C. jejuni, to the chicken gut, thus lowering the public health risk from contaminated muscle and liver tissues.
Building on our recent BBSRC-funded work showing that C. jejuni found in UK broiler chicken production form a diverse population in terms of in vivo behaviour in broilers and impacts on bird and public health, our focus will be on those strains that are able to colonise the upper chicken gut and from there spread to edible tissues. We seek to lessen the public health and bird-health threats associated with extra-intestinal spread of C. jejuni. It is likely that our work will also help to lower levels in the broiler intestine.
By addressing a major public-health threat, the interventions that will be developed from our findings have potential to reduce the estimated 700000 cases of infection in the UK annually (with around 100 deaths, mainly in elderly people). The economic benefit of reducing the estimated £1 billion plus annual cost of chicken-associated Campylobacter infection to the UK economy will be allied to financial benefits for the broiler industry that will flow from any intervention to address a cause of reduced bird performance. Moreover, the poultry-industry supply sector will see economic benefits through bringing to market products associated with these interventions, for which demand will be global and will increase as populations grow and developing nations intensify their broiler production. Finally, bird welfare will be improved, a worthwhile outcome in its own right and of particular importance in a society that places high value on animal welfare.