Pushing the Envelope - Deciphering the Salmonella Typhimurium Envelope Stress Response.

孩子、房子、工作——生活的压力有时对我们来说太大了，但总的来说，我们适应了我们的环境，对挑战做出了反应——沙门氏菌也是如此。从凉爽夏夜农民地里的莴苣到人胃里的酸性环境，在这两者之间的每一个生命周期阶段，沙门氏菌都会遇到非常不同的压力环境。为了生存，他们必须能够在正确的时间部署适当的武器。这些武器既可以对抗压力，也可以修复压力造成的损害。这就是沙门氏菌成为人类和动物如此成功的病原体的原因之一。细胞包膜——像沙门氏菌这样的细菌与其周围环境之间的界面——提供了两个主要功能。一种结构上对恶劣环境的保护作用，一种感知/信号作用，使沙门氏菌知道它暴露在什么环境中，并能做出相应的反应。当沙门氏菌暴露在抗生素或温度冲击下导致细胞包膜受损时，它会打开一种特定类型信号通路的开关，包膜应激反应（ESR）就会启动——但是为什么只有一种途径，而你可以有两种或三种途径呢？沙门氏菌的ESR至少包括三条途径。其中两种是由RpoE和CpxRA调控的。我们之前已经证明了在感染期间这些调节因子对沙门氏菌的重要性。由BaeSR调控的第三种途径在所有细菌中都知之甚少。本提案旨在通过找出BaeSR规范的过程来提高我们对ESR的理解。我们还将绘制出这三种途径重叠的点，因为我们认为这些重叠的基因对感染非常重要。我们对ESR的描述是确定消除人类和猪沙门氏菌的新疫苗和抗生素靶点的途径。为什么我们需要新的抗沙门氏菌疫苗和抗生素？沙门氏菌在人类中引起两种主要疾病。持续一周的胃肠炎（食物中毒）和一种全身性疾病，如伤寒，如果不治疗可能会致命。沙门氏菌作为一种病原体的成功可以通过每年它引起的病例数量来衡量。尽管在英格兰和威尔士食源性沙门氏菌病例的数量目前正在下降，但沙门氏菌在英国造成的死亡人数仍然超过任何其他食源性病原体，世界卫生组织估计每年有1600万例伤寒病例和60万人死亡。再加上抗生素耐药性的负担不断增加，这意味着我们必须确定新的疫苗和抗生素目标，以便从食物链中根除沙门氏菌，并治疗/保护居住在伤寒流行地区的人们免受伤寒的侵害。使用疫苗将沙门氏菌从食物链中清除的成功程度可以通过鸡的疫苗接种来衡量——用超市鸡蛋上的狮子标记来表示。这就是前面提到的沙门氏菌食物中毒下降的原因。英国的猪群是鼠伤寒沙门氏菌的巨大储存库，23%的英国猪携带沙门氏菌，而且它们目前没有接种疫苗。猪肉是欧洲消费最多的肉类，与猪肉有关的沙门氏菌食物中毒正在增加。猪体内的沙门氏菌需要根除。我们已经确定了沙门氏菌RpoE和CpxRA包膜应激反应途径的成员，它们已显示出作为疫苗靶点的希望。我们还表明，这些反应的几个成员是细菌特异性酶，一种蛋白质，使优秀的药物靶标。凭借我们以前的知识和专业知识，结合我们将使用的多学科方法，我们可以真正推动极限！

The kids, the house, the job - the stresses of life can be too much for us all sometimes but on the whole we adapt to our circumstances and respond to the challenge - so does the bacterium Salmonella. From a lettuce in a farmer's field on a cool summer's night to the acidic conditions of the human stomach, and every life cycle stage in between, Salmonella encounters very different stressful situations. In order to survive they must be able to deploy the appropriate weapons at the right time. These weapons can either combat the stress or repair the damage that the stress has caused. That is one of the reasons why Salmonella is such a successful human and animal pathogen. The cell envelope - the interface between a bacterium like Salmonella and its surroundings - provides two major functions. A structurally protective role against harsh environments and a sensing/signalling role so that Salmonella knows what it is being exposed to and can respond accordingly. When Salmonella is exposed to say antibiotics or temperature shock that cause damage to this cell envelope it flicks the switch on a particular type of signalling pathway and the envelope stress response (ESR) springs into action - but why have only one pathway when you can have two or three? The ESR of Salmonella consists of at least three pathways. Two are well characterised and are regulated by RpoE and CpxRA. We have previously demonstrated the importance of these regulators to Salmonella during infection. The third pathway regulated by BaeSR is poorly understood in all bacteria. This proposal aims to improve our understanding of the ESR through finding out the processes that BaeSR regulates. We will also map out the points that these three pathways overlap - as we think that these overlapping genes will be extremely important for infection. Our characterisation of the ESR is a route to identifying new vaccine and antibiotic targets for elimination of Salmonella from humans and pigs. Why do we need new anti-Salmonella vaccines and antibiotics? Salmonella causes two main disease types in humans. An unpleasant bout of gastroenteritis (food poisoning) which lasts around a week and a systemic disease, Typhoid fever, which can be deadly if untreated. The success of Salmonella as a pathogen can be measured by the number of cases it causes each year. Although the number of foodborne Salmonella cases in England and Wales is currently on the decline, Salmonella is still responsible for more deaths in the UK than any other foodborne pathogen, and Worldwide, WHO estimate 16 million cases of Typhoid fever and 600,000 deaths per annum. This combined with the forever increasing burden of antibiotic resistance means it is essential that we identify new vaccine and antibiotic targets which would allow eradication of Salmonella both from the food chain and to treat/protect people residing in endemic areas from Typhoid fever. The success of using a vaccine to remove Salmonella from the food chain can be measured by the vaccination of chickens - denoted by the lion mark on your supermarket eggs. This is the reason for the aforementioned decline in Salmonella food poisoning. The Great Britain pig population is a huge reservoir of Salmonella Typhimurium with 23% GB pigs carrying Salmonella - and they are not currently vaccinated. Pork is the most consumed meat in Europe and pork associated Salmonella food poisoning is on the increase. Salmonella in pigs needs to be eradicated. We have already identified members of the RpoE and CpxRA envelope stress response pathways of Salmonella which have shown promise as vaccine targets. We have also shown that several members of these responses are bacterial specific enzymes, a type of protein that makes excellent drug targets. Armed with our previous knowledge and expertise, combined with the multi-disciplinary approach we will use, we can really push the envelope!