Molecular mechanisms underlying Campylobacter jejuni's unusual swimming style

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The bacterium Campylobacter jejuni causes food poisoning. In the UK Campylobacter causes more food poisoning than any other bacteria including E. coli or Salmonella (the Food Standards Agency estimates that Campylobacter infections cost us almost one billion pounds per year). Campylobacter is also very similar to other types of 'dangerous' bacteria that cause other stomach problems, including cancers. If we can understand these bacteria better, we'll be better able to develop drugs to fight them. This grant proposes a programme of experiments Campylobacter to understand swimming in this dangerous bacterium; because they need to be able to swim to cause infection, we may be able to develop drugs that "jam" their swimming, in the process halting infection.Most dangerous bacteria need to be able to swim to cause their disease, but Campylobacter swims in a very unusual manner. Many bacteria 'swim' using a miniature motor that sits in the skin of the bacterium. On the end of the motor's driveshaft is a long tail that spun by the motor; the spinning long tail coils to become a helical propeller, pushing the bacterium through its fluid habitat. Campylobacter uses the same tail, but swims in a very different way to other bacteria, and this may prove to be its Achilles heal: we may in the future develop targeted drugs that only affect Campylobacter and close relatives. Specifically, Campylobacter uses two very powerful motors to swim, one at each end of the cell. Because the two motors are at opposite ends of the cell, they potentially push in opposite directions. Campylobacter has developed a way to combine their thrust productively: one motor "pushes" from behind, while the leading motor coils its tail around Campylobacter's helical cell body to "pull" from in front. But we don't understand how Campylobacter is able to do this. If we can better understand the biology of this curious swimming we may be able to make drugs to prevent it.To understand bacterial swimming, it is essential to be able to see the motor, see the helical tail, and see the shape of the cell, which are difficult things to do. I believe this is absolutely essential, so to visualize bacteria my "research co-investigator" and I have trained in techniques that enable us to directly see them inside the cell, to see the molecular details of the motor that drives swimming, and to collect videos of bacteria swimming in action. To help us fully understand our data we've recruited a stellar team of international scientists, many of whom we have long-standing collaboratory relationships with.We're still some way from using these results to fight Campylobacter food poisoning. If we had a detailed understanding of how Campylobacter swims, however, we might start designing drugs that stop it swimming. This MRC proposal requests funds to perform this research.We propose three aims:One: A few years ago we published findings that the Campylobacter motor has evolved to be much more powerful than other motors, and this allows it to swim through viscous mucous in our guts to cause food poisoning. Our more recent findings, however, suggest we were naïve: while likely correct, the motor is also probably intimately involved in the unwrapping process. We will test this hypothesis and understand more about its structure in the process.Two: We will test hypotheses that Campylobacter's long tail has evolved to specifically enable wrapping around the cell body. We will go as far as to deduce the ancestral state, which will provide us with in-depth fascinating insights into precisely which aspects of the tail contribute to wrapping.Three: Our recent findings suggest that it is not only the motor and tail that contribute to wrapping and unwrapping, but also interactions with the helical cell body of Campylobacter. We will test this hypothesis and characterize factors leading to this.