Molecular mechanisms underlying Campylobacter jejuni's unusual swimming style

空肠弯曲杆菌是一种引起食物中毒的细菌。在英国，弯曲杆菌引起的食物中毒比大肠杆菌或沙门氏菌等其他细菌更多(例如，食品标准局估计，弯曲杆菌感染每年给我们造成的损失近10亿英镑)。弯曲杆菌也与其他会导致其他胃部疾病(包括癌症)的“危险”细菌非常相似。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。这项拨款提案以弯曲杆菌为例，了解在这种危险细菌家族中游泳。大多数危险细菌需要能够游泳才能导致它们的疾病，而弯曲杆菌以一种非常不寻常的方式游泳。大多数细菌利用位于细菌皮肤内的微型马达“游泳”。在马达传动轴的末端是一条马达旋转的长尾；旋转的长尾卷起成为螺旋桨，推动细菌通过其液体栖息地。弯曲杆菌(和家族成员)使用相同的尾巴，但游泳的方式与其他细菌截然不同，这可能被证明是它的致命弱点：我们或许能够开发出只影响弯曲杆菌和家族的靶向药物。具体来说，弯曲杆菌使用一个非常强大的马达来游泳。它还使用这个强大的马达来旋转它的身体，它的身体形状像开瓶器一样，使它能够很容易地进入非常稠密的液体中，如肠道粘液，因此更容易导致疾病。但我们不明白弯曲杆菌是如何做到其中许多事情的。如果我们能更好地了解这种奇怪游泳的生物学，我们就可能制造药物来预防它。要了解细菌游泳，能够看到发动机和细胞的形状真的很重要，这是一项艰巨的任务。我相信这是绝对必要的，所以要可视化我用一种技术训练的细菌，这种技术使我们能够直接看到它们在细胞内，以及驱动游泳的马达的分子细节。为了帮助我充分理解这个项目的图像，我招募了一个由国际科学家组成的明星团队。我们距离利用这些结果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一个详细的了解，我们可能会开始设计阻止它游泳的药物。MRC的这项提案要求资金来进行这项研究，我提出了四个目标：第一：弯曲杆菌实际上制造了两个马达，但只使用其中一个(如果两者都使用，它们就会朝着相反的方向推进！)我将使用我的成像技能来观察活跃和不活跃的马达，以了解其中的区别--反过来，告诉我们它是如何工作的。如果我们能理解一个马达是如何失活的，或许我们可以制造药物来灭活这两个马达？第二：弯曲杆菌通过旋转尾巴和细胞体来游泳。我想我知道它如何在两者之间分配游泳力，并将对此进行测试。三：弯曲杆菌如何使自己变成螺旋形？我将收集图像来了解这一点。第四：最后，我将与合作者合作开发一个数学模型，将所有先前的结果结合在一起，以了解所有因素是如何结合在一起产生弯曲杆菌独特的游泳能力的。

Campylobacter jejuni is a bacterium that causes food poisoning. In the UK Campylobacter causes more food poisoning than other bacteria such as E. coli or Salmonella (e.g, the Food Standards Agency estimates that Campylobacter infections cost us almost one billion pounds per year). Campylobacter is also very similar to other '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 proposal uses Campylobacter as an example to understand swimming in this family of dangerous bacteria.Most dangerous bacteria need to be able to swim to cause their disease, and Campylobacter swims in a very unusual manner. Most 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 the motor spins; the spinning long tail curls up to become a helical propeller, pushing the bacterium through its liquid habitat. Campylobacter (and family members) 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 be able to develop targeted drugs that only affect Campylobacter and family. Specifically, Campylobacter uses a single very powerful motor to swim. It also uses this powerful motor to rotate its body, which is shaped like a corkscrew, allowing it to 'bore' into very thick fluids such as gut mucous easily, and therefore is better able to cause disease. But we don't understand how Campylobacter is able to do many of these things. 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's really important to be able to see the motor and the shapes of the cell, which is a difficult task. I believe this is absolutely essential, so to visualize bacteria I trained in a technique that enables us to directly see them inside the cell, and the molecular details of the motor that drives swimming. To help me fully understand the images from this project I've recruited a stellar team of international scientists.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.I propose four aims:One: Campylobacter actually makes two motors, but only uses one of them (if it used both, they'd push in opposite directions!). I'll use my imaging skills to see both the active and inactive motors to understand what the difference is - in turn, telling us how it works. If we can understand how one motor is inactivated, maybe we can make drugs to inactivate both motors?Two: Campylobacter swims by rotating both its tail, and its cell body. I think I know how it divides the amount of swimming power between the two, and will test this.Three: How does Campylobacter make itself helical-shaped? I'll collect images to make progress towards understanding this.Four: Finally, I'll team up with collaborators to develop a mathematical model to combine all previous results to understand how all factors combine to produce the unique swimming of Campylobacter.