Molecular mechanisms underlying Campylobacter jejuni's unusual swimming style

空肠弯曲杆菌会引起食物中毒。在英国，弯曲杆菌引起的食物中毒比包括大肠杆菌或沙门氏菌在内的任何其他细菌都要多（食品标准局估计，弯曲杆菌感染每年给我们造成近10亿英镑的损失）。弯曲杆菌也与其他类型的“危险”细菌非常相似，这些细菌会导致其他胃部问题，包括癌症。如果我们能更好地了解这些细菌，我们就能更好地开发出对抗它们的药物。这项拨款提出了一项弯曲杆菌实验计划，以了解在这种危险细菌中游泳；因为它们需要能够游泳才能引起感染，我们也许能够开发出“干扰”它们游泳的药物，在这个过程中阻止感染。大多数危险的细菌需要能够游泳才能致病，但弯曲杆菌以一种非常不寻常的方式游泳。许多细菌使用位于细菌皮肤中的微型马达“游泳”。在电机传动轴的末端有一条由电机旋转的长尾；旋转的长尾盘绕成一个螺旋螺旋桨，推动细菌穿过它的液体栖息地。弯曲杆菌使用相同的尾巴，但与其他细菌的游泳方式非常不同，这可能被证明是它的阿喀琉斯愈合：我们可能在未来开发出仅影响弯曲杆菌及其近亲的靶向药物。具体来说，弯曲杆菌使用两个非常强大的马达来游泳，一个在细胞的两端。因为两个马达位于细胞的两端，它们可能会向相反的方向推动。弯曲杆菌已经开发出一种有效地结合它们的推力的方法：一个马达从后面“推动”，而领先的马达将它的尾巴缠绕在弯曲杆菌的螺旋细胞体上，从前面“拉动”。但我们不明白弯曲杆菌是如何做到这一点的。如果我们能更好地了解这种奇特游泳的生物学原理，我们也许就能制造药物来预防它。为了了解细菌的游动，必须能够看到马达，看到螺旋状的尾巴，看到细胞的形状，这些都是很难做到的。我相信这是绝对必要的，所以为了可视化细菌，我和我的“研究合作研究者”接受了技术训练，使我们能够直接看到细胞内的细菌，看到驱动游泳的马达的分子细节，并收集细菌游泳的视频。为了帮助我们充分理解我们的数据，我们招募了一支优秀的国际科学家团队，其中许多人与我们有着长期的合作关系。我们距离利用这些结果来对抗弯曲杆菌食物中毒还有一段路要走。然而，如果我们对弯曲杆菌如何游泳有了详细的了解，我们就可以开始设计药物来阻止它游泳。这项MRC提案要求资金来进行这项研究。我们提出了三个目标：第一，几年前我们发表了一项研究结果，弯曲杆菌的马达已经进化得比其他马达强大得多，这使得它可以在我们肠道中的粘性粘液中游动，导致食物中毒。然而，我们最近的发现表明我们是naïve：虽然可能是正确的，但马达也可能密切参与了打开包裹的过程。我们将在这个过程中检验这个假设，并进一步了解它的结构。二：我们将验证弯曲杆菌的长尾巴已经进化到能够包裹细胞体的假设。我们将推断出祖先的状态，这将为我们提供深入而迷人的见解，确切地说，尾巴的哪些方面有助于缠绕。三：我们最近的研究结果表明，弯曲杆菌的缠绕和解开不仅是马达和尾巴的作用，还与螺旋细胞体的相互作用有关。我们将检验这一假设，并描述导致这种情况的因素。

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.