Molecular mechanisms underlying Campylobacter jejuni's unusual swimming style

空肠弯曲杆菌不寻常游泳方式的分子机制

• 批准号: MR/P019374/1
• 负责人: Morgan Beeby
• 金额: $ 54.28万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP019374%2F1
• 关键词: Molecular; mechanisms; underlying; Campylobacter; jejuni

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.

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其他细菌，如大肠杆菌。大肠杆菌或沙门氏菌（例如，食品标准局估计弯曲杆菌感染每年花费我们近10亿英镑）。弯曲杆菌也非常类似于其他“危险”的细菌，导致其他胃病，包括癌症。如果我们能更好地了解这些细菌，我们将能够更好地开发药物来对抗它们。这项拨款提案以弯曲杆菌为例，以了解这个危险细菌家族中的游泳。大多数危险细菌需要能够游泳才能引起它们的疾病，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中的微型马达“游泳”。在马达驱动轴的末端有一条长长的尾巴，马达可以旋转;旋转的长尾卷曲成螺旋桨，推动细菌穿过它的液体栖息地。弯曲杆菌（及其家族成员）使用相同的尾巴，但以与其他细菌截然不同的方式游动，这可能是它的致命弱点：我们可能能够开发出只影响弯曲杆菌及其家族的靶向药物。具体来说，弯曲杆菌使用一个非常强大的马达来游泳。它还使用这种强大的马达来旋转它的身体，它的形状像一个开瓶器，使它能够很容易地“钻”进非常粘稠的液体，如肠道粘液，因此更容易引起疾病。但我们不明白弯曲杆菌是如何做到这些的。如果我们能更好地了解这种奇特游动的生物学原理，我们也许能制造出药物来阻止它。为了了解细菌游动，能够看到细胞的运动和形状非常重要，这是一项艰巨的任务。我相信这是绝对必要的，所以为了可视化细菌，我训练了一种技术，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。为了帮助我完全理解这个项目的图像，我已经招募了一个国际科学家组成的一流团队。我们离使用这些结果来对抗弯曲杆菌食物中毒还有一段距离。然而，如果我们对弯曲杆菌如何游动有了详细的了解，我们可能会开始设计阻止它游动的药物。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（如果它使用两个，它们会向相反的方向推动！）我将用我的成像技巧来观察活跃和不活跃的马达，以了解它们的区别--反过来，告诉我们它们是如何工作的。如果我们能理解一个马达是如何失活的，也许我们可以制造出抑制两个马达的药物？第二：弯曲杆菌通过旋转它的尾巴和它的细胞体来游泳。我想我知道它是如何在两者之间分配游泳的力量的，我将测试这个。第三：弯曲杆菌是如何使自己成为螺旋形的？我会收集图像来进一步理解这一点。第四：最后，我将与合作者合作开发一个数学模型，将所有以前的结果联合收割机结合起来，以了解所有因素联合收割机是如何结合起来产生弯曲杆菌独特的游动。

项目成果

?-proteobacteria eject their polar flagella under nutrient depletion, retaining flagellar motor relic structures

β-变形菌在营养耗尽时弹出极鞭毛，保留鞭毛运动遗迹结构

• DOI: 10.1101/367458
• 发表时间: 2018
• 作者: Ferreira J

Campylobacter jejuni motility integrates specialized cell shape, flagellar filament, and motor, to coordinate action of its opposed flagella.

• DOI: 10.1371/journal.ppat.1008620
• 发表时间: 2020-07-01
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Cohen, Eli J;Nakane, Daisuke;Beeby, Morgan
• 通讯作者: Beeby, Morgan