Dissecting the role of the Campylobacter haem uptake system in host colonisation and disease

铁是细菌在细胞中许多基本过程所需要的营养物质。作为对细菌感染反应的一部分，动物限制铁的可用量。在哺乳动物中，乳铁蛋白（在粘膜分泌物中）和转铁蛋白（在血清中）紧密结合游离铁以限制其可用性。不幸的是，成功致病的细菌已经找到了从宿主那里夺回铁的方法。细菌在宿主体内获取铁的机制通常包括细菌细胞外表面的一个特定孔和一个相关的运输系统，使铁在细胞内可用。最重要的与食物有关的细菌是弯曲杆菌，它会感染人类，因此在英国造成了许多痛苦和经济损失。弯曲杆菌通常生活在许多动物的肠道中，尤其是鸡，在那里它们并不总是引起疾病。然而，当人类食用被弯曲杆菌污染的食物时，就会出现非常不愉快的痉挛腹泻。食品生产商努力将消费者食物中毒的风险降至最低，但如果能从农场动物（尤其是鸡）的肠道中清除弯曲杆菌，它将通过每年预防成千上万例食源性疾病，对人类健康产生重大影响。如果要实现控制，重要的是我们要更好地了解弯曲杆菌是如何在肠道中定植的。弯曲杆菌的一些成分对肠道生长至关重要，它们参与了在宿主体内获取铁的过程。在我们的初步工作中，我们已经确定并开始描述弯曲杆菌中的一个系统，该系统可以直接从血红素中获取铁来支持细菌生长。血红素是一种假体基团，或蛋白质的非氨基酸成分，对蛋白质的生物活性很重要，含有铁。弯曲杆菌血红素摄取系统（Chu）包括一个将血红素导入细胞的表面孔（ChuA）和一种从血红素中去除铁的酶（ChuZ）。Chu系统在弯曲杆菌分离株中高度保守。相比之下，其他铁吸收孔，即CfrA和Cj0178，被认为在某些菌株中是必需的，但在其他菌株中不存在。我们的第一个任务是确定哪些成分在缺乏CfrA和Cj0178的菌株中获得铁的作用；这些组分包括楚孔和Cj0444孔。我们的第二个任务是进一步研究ChuA孔如何从蛋白质中去除血红素群，并对ChuZ如何工作进行更详细的描述，包括计算出蛋白质的结构。随着对弯曲杆菌铁获取系统的更好了解，我们将能够确定它们是否会成为农场干预的一个有吸引力的目标，以阻止动物肠道的生长并减少食品污染。

Iron is a nutrient that bacteria need for many essential processes in the cell. As part of the response to infection by bacteria, animals restrict the amount of iron available. In mammals lactoferrin (in mucosal secretions) and transferrin (in serum) tightly bind free iron to restrict its availability. Unfortunately, successful disease-causing bacteria have found ways to grab iron back from the host. The bacterial mechanisms involved in acquiring iron in the host usually consist of a specific pore on the outer surface of the bacterial cell and an associated transport system that makes the iron available inside the cell. The most important food-associated bacterium, which infects humans, is Campylobacter and as such is responsible for much misery and economic loss in the UK. Campylobacters normally live in the intestine of many animals, notably chickens, where they do not always cause disease. However, when humans eat food contaminated with campylobacters, a highly unpleasant cramping diarrhoea can follow. Food producers strive to minimise the risks of food poisoning for consumers, but if Campylobacter could be eliminated from the intestines of farm animals, particularly chickens, it would have a significant impact on human health by preventing many thousands of cases of food borne disease each year. If control is to be achieved it is important that we better understand how Campylobacter colonises the intestine. Several components of campylobacters that are essential for growth in the intestine are involved in acquiring iron within the host. In our preliminary work, we have identified and begun to characterise a system in campylobacters that can grab iron directly from haem to support bacterial growth. Haem is a prosthetic group, or non-amino acid component of a protein that is important in the protein's biological activity, that contains iron. The Campylobacter Haem Uptake system, or Chu, includes a surface pore (ChuA) that imports haem into the cell and an enzyme (ChuZ) that removes iron from haem. The Chu system is highly conserved in isolates of Campylobacter. In contrast, other iron uptake pores, namely CfrA and Cj0178, are thought to be essential in some strains but are not present in others. Our first task is to determine which components play a role in acquiring iron in those strains where CfrA and Cj0178 are absent; these components include the Chu and Cj0444 pores. Our second task is to further investigate how the ChuA pore removes the haem group from proteins and to carry out a more detailed characterisation of how ChuZ works, including working out the structure of the protein. With a better understanding of Campylobacter iron acquisition systems we will be able to determine if they would be an attractive target for intervention on the farm in order to block growth in the animal gut and reduce food contamination.