Topical issues:

Fighting Campylobacter food poisoning

The bacterium Campylobacter is the most common cause of food poisoning in the UK; responsible for an estimated 321,000 cases in 2008 [see footnote 1]. For most people the infection is 'self-limiting' with symptoms lasting for only a few days, but on rare occasions there are very serious, even fatal, complications.

Contaminated poultry meat is the major source of Campylobacter infection but other sources include other raw meats, unpasteurised milk and contaminated water.

Much of BBSRC's funding for research into the biology of Campylobacter addresses two inter-related issues:

Click to read more about reducing the reservoir
Reducing the 'reservoir'
© Creatas
Click to read more about understanding virulence
Understanding virulence
© Society for General Microbiology

Reducing the reservoir

An estimated 65% of raw chicken carcasses carry Campylobacter bacteria [see footnote 2]. We need to reduce levels of Campylobacter contamination on farms, and throughout the food production chain. Particular problems arise from the bacterium's ability to survive in a variety of environments. This means that Campylobacter can be a cause of infection from sources as different as live animals, raw meat, water and surfaces. We also need to know why poultry are so susceptible to carriage of Campylobacter jejuni and Campylobacter coli - the two species that are the principal cause of human gastroenteritis worldwide.

Why do so many birds carry Campylobacter?
How does Campylobacter protect itself from host immune defences?
Why does Campylobacter spread so easily from bird to bird?
How does Campylobacter adapt its metabolism in order to survive in different environments?
Can we predict and model Campylobacter colonisation in poultry?
What can we do to control Campylobacter in poultry flocks?

Why do so many birds carry Campylobacter?

C. jejuni and C. coli are highly adapted to life inside the poultry gut. Recent research at the London School of Hygiene and Tropical Medicine and The Pirbright Institute, formerly the Institute for Animal Health, has shown how the genetic make-up of these two strains of the bacterium makes them better suited to colonising their poultry hosts compared with other Campylobacter strains.

Comparisons between strains of Campylobacter associated with infection in chicken and ones that are not, suggest that genes involved in producing sugar-based structures on the flagellum (tail) of the bacterium are important for colonising the chicken gut. Naturally variable forms of these genes appear to contribute to the different colonising abilities of different strains of Campylobacter.

Campylobacter co-exists and interacts with other species of bacteria that are resident in the poultry gut. By analysing the metabolism of Campylobacter, scientists at the University of Sheffield and the Institute of Food Research (IFR) have shown that the bacterium is able to use organic acid metabolites produced by the gut microflora. Optimising its metabolism to use amino acids and other carbon sources available in the poultry gut, contributes to life-long colonisation.

The genetic makeup of poultry can also affect the ability of Campylobacter to colonise poultry. Scientists at IAH, the Roslin Institute (RI) and the University of Edinburgh have identified four regions of the chicken genome that are associated with resistance to Campylobacter.

The idea is to use this knowledge of poultry and Campylobacter genetics and of the molecular interactions between colonising bacteria and the host’s immune system to help design new control strategies, including opportunities for breeding poultry for disease resistance.

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How does Campylobacter protect itself from host immune defences?

Far from being a true commensal that goes unseen by the host’s immune response, scientists at the University of Nottingham, IAH and RI have identified that infected poultry produce pro-inflammatory immune responses to Campylobacter, and that the bacterium can be killed by avian macrophages (a type of white blood cell).

Macrophages engulf bacteria and kill them with nitric oxide. For Campylobacter to survive, it must be able to detect and then protect itself against nitric oxide. How it does so is being investigated by scientists at the Universities of Sheffield and Surrey. They have found a small suite of genes that respond specifically to the presence of nitric oxide, and are now characterising these to identify the role each has in enabling Campylobacter to survive inside macrophages.

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Why does Campylobacter spread so easily from bird to bird?

Chickens that are ‘stressed’, for example, as a result of transportation, and chickens that already have infections in their gut appear to be more susceptible to infection by Campylobacter. In these cases, the infected birds excrete higher than usual numbers of the bacteria, so infection can spread even more rapidly than usual.

Scientists at the Universities of Liverpool, Leicester and IFR are working together to identify how stress and pre-infection have these effects. One theory is that they compromise the bird’s immune system, which in turn increases the ability of Campylobacter to be more ’invasive’ (pathogenic).

This raises the possibility that Campylobacter can respond to stress-associated hormones in its host by changing into a more virulent form capable of crossing out of the gut and into other tissues. This might explain why some chicken carcasses carry Campylobacter not just on their surfaces but deep inside the muscle where they survive better-DEFINE if cooking is inadequate.

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How does Campylobacter adapt its metabolism in order to survive in different environments?

Campylobacter bacteria need oxygen but cannot grow at the levels of oxygen found in the air. The response of the organisms to different levels of oxygen is only poorly understood. Scientists at the University of Sheffield and IFR are characterising how Campylobacter senses levels of oxygen and how it switches production of some proteins on or off to tailor its respiration to its environment

Campylobacter cannot metabolise glucose and other sugars, instead they are dependent on other carbon sources found in their environment to sustain growth. Researchers at the University of Sheffield, IFR and IAH, have found that, in the low oxygen environment of the gut, C. jejuni metabolism is limited to a small range of amino acids. Mutant strains, which lack the ability to metabolise the amino acids serine and aspartic acid, do not colonise well.

A team at IFR has found that when exposed to air, Campylobacter bacteria rapidly attach to a surface and encase themselves in a sticky ‘biofilm’. This is an example of the bacterium’s ability to sense and respond quickly to stresses in its environment and may partly explain how Campylobacter infections are spread. The research showed that Campylobacter cells are shed from the biofilm and this suggests that they could subsequently enter the food chain.

Understanding more about oxygen sensing and biofilm formation will help to inform development of new antimicrobials and suggest ways to prevent Campylobacter build-up on surfaces.

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Can we predict and model Campylobacter colonisation in poultry?

Campylobacter bacteria colonise and live in the intestinal tracts of poultry but few of the birds show any signs of illness. Colonisation by Campylobacter is surprisingly complex.

A team of scientists from the Universities of Cambridge and Nottingham and IAH have found that even in the simplest case of competition between two strains of Campylobacter, it is impossible to predict the precise population structure in the gut both within and between individual birds. However, the strain that colonises the gut first and other factors associated with bird-to-bird transmission seem to play an important role in determining the population composition. More broadly, the studies have helped to show the level of bacteria that are required to establish stable populations within the avian intestines and to transmit effectively between co-housed birds.

Researchers at Cambridge, Leeds and Pennsylvania State University, USA are also working together to simulate the growth and survival dynamics of Campylobacter between and within birds. Predictive models of colonisation will aid risk assessment and the design of control measures to reduce levels of contamination, and, importantly, how effective these control strategies need to be.

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What can we do to control Campylobacter in poultry flocks?

There are many different strains of Campylobacter jejuni. To be effective, control agents need to have a broad spectrum of activity. They should also be ‘durable’, i.e. not easily overcome by the bacteria evolving resistance mechanisms against them.

Researchers at IAH and the Universities of Cambridge and Nottingham recently evaluated a Salmonella vaccine that contained a specific C. jejuni protein called CjaA. Despite producing CjaA-specific antibodies, the levels of C. jejuni in treated birds fell by only a small amount, and the ‘protective effect’ was not seen until late in life (after most broilers are killed for meat).

Although only a small reduction was observed, this may be sufficient to reduce spread through flocks and the food chain and could be evaluated with further modelling studies. The team is now looking at other transporter proteins, similar to CjaA, as a means of developing multivalent vaccines to overcome potential problems of serotype resistance.

In theory, it is possible to control Campylobacter in flocks of poultry by using bacteriophages – naturally occurring viruses that attack bacteria.

In experiments at the University of Nottingham, scientists have successfully reduced the numbers of Campylobacter bacteria in infected chickens by treating them with bacteriophages. They have also compared flocks in which the ‘phages’ are readily found with those in which they are not, and showed that the former carry lower numbers of Campylobacter.

Interestingly, it seems that Campylobacter phages show adaptations to their poultry host and possess genes that may enhance Campylobacter metabolism, potentially advantaging both the phage and its host.

What’s more, the genomes of the Campylobacter phages they studied appear to be highly adapted to attack this species, and a wider investigation showed that the genomes of other Campylobacter phages had important sequence similarities, suggesting that they can be stable over prolonged periods of time, making them strong candidates as control agents.

Researchers at Cambridge have shown that different Campylobacter phages target different bacterial surface structures, an observation that should also be considered when selecting phages for activity against a broad range of Campylobacter isolates.

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Understanding virulence

We need to know more about how Campylobacter causes food poisoning and how, for example, infection can cause two different types of symptoms in people: inflammatory diarrhoea or watery diarrhoea. We can expect that a greater understanding of the mechanisms of virulence will reveal new targets for preventing and controlling infection.

Why do foodborne pathogens such as Campylobacter behave differently in their poultry hosts and the human gut?
What do we know about the role of the flagellum in virulence?
How does Campylobacter hijack host transport systems to further its cause?
What can genomic studies tell us about the pathogenic potential of Campylobacter?

Why do foodborne pathogens such as Campylobacter behave differently in their poultry hosts and the human gut?

Typically, bacteria cause infection through the action of toxins and other invasive proteins that they secrete. Joint research by scientists at the Moredun Research Institute and University of Glasgow is investigating the effects of secreted proteins on cells lining the gut.

The Glasgow group is also studying the symptoms in pigs that are infected with different genetic variants of C. jejuni, as a guide to understanding the basis of the human conditions. The aim is to identify key molecules that are present in some strains but not in others, and to correlate the presence of these molecules with the particular type of infection caused.

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What do we know about the role of the flagellum in virulence?

The flagellum is the tail-like structure at one or both ends of Campylobacter. It is not only important in bacterial motility and colonisation, but also important in virulence because it provides a channel for the secreted toxins and other virulence factors.

Researchers at the University of Birmingham use variants of C. jejuni that lack one or more genes to see how the loss of gene function affects the organism’s ability to produce functional flagella.

They have identified two essential genes and are exploring how these are regulated within Campylobacter and how they interact with other genes that influence flagellar location and function.

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How does Campylobacter hijack host transport systems to further its cause?

Obtaining adequate iron from inside their hosts is a common problem for disease-causing bacteria. Cells in the animal gut store their own supply of iron by binding it tightly to carrier proteins, and invading pathogens compete for iron with the normal gut microflora.

Campylobacter is able to ‘steal’ iron from carrier proteins inside avian and human cells. At the University of Leicester scientists are identifying the molecules involved in enabling the bacteria to interact with receptor molecules and iron transporter mechanisms in the host cell membranes. They are also exploring how different strains of Campylobacter deploy different mechanisms for iron uptake, which allows them to exploit a variety of iron sources found in different host environments and could indicate the importance of iron in the progression of disease in the human host.

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What can genomic studies tell us about the pathogenic potential of Campylobacter?

When the complete sequence of the Campylobacter chromosome was published in 2000, one of the findings was that, when compared to bacteria such as Escherichia coli and Salmonella, Campylobacter seemed to have a limited capability to control expression of its genes in response to external stimuli, for example the stresses encountered in the food chain and in the human and avian intestine. As this is in stark contrast to the success of Campylobacter as a foodborne pathogen, it was predicted that Campylobacter may use as yet undescribed mechanisms to control expression of its genetic potential encoding virulence and metabolism.

At IFR, scientists are using advanced DNA sequencing technologies to map novel features of the Campylobacter chromosome, and have already shown that this chromosome is much more complex than originally thought, with many novel features including bacterial versions of RNA interference known from mammals and plants. These novel features will be further investigated, in collaboration with the Genome Analysis Centre utilising the centre’s large scale next generation DNA sequencing and bioinformatics capabilities.

footnote 1: 2008 Defra Zoonoses report

footnote 2: FSA publishes survey of campylobacter and salmonella in chicken – http://www.food.gov.uk/news/newsarchive/2009/oct/chicksurvey 

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