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所有人来说都太大了，但总的来说，我们会适应环境，应对挑战--沙门氏菌也是如此。从凉爽的夏夜农民田地里的生菜到人类胃的酸性条件，以及其间的每个生命周期阶段，沙门氏菌都会遇到非常不同的压力情况。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。这就是为什么沙门氏菌是如此成功的人类和动物病原体的原因之一。细胞被膜--沙门氏菌等细菌与其周围环境之间的界面--提供了两个主要功能。对恶劣环境的结构保护作用和传感/信号作用，使沙门氏菌知道它正在暴露于什么，并可以相应地作出反应。当沙门氏菌暴露于抗生素或温度冲击，导致这种细胞包膜受损时，它会触发一种特定类型的信号通路，包膜应激反应（ESR）就会发生作用-但为什么只有一种通路，而你可以有两种或三种？沙门氏菌的ESR至少由三条途径组成。其中两种被很好地表征，并由RpoE和CpxRA调节。我们先前已经证明了这些调节剂在感染期间对沙门氏菌的重要性。BaeSR调控的第三条途径在所有细菌中都知之甚少。本提案旨在通过找出BaeSR调节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的表征是确定新疫苗和抗生素靶点以消除人和猪沙门氏菌的途径。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。一种令人不快的肠胃炎（食物中毒），持续大约一周，还有一种全身性疾病，伤寒，如果不治疗可能致命。沙门氏菌作为病原体的成功可以通过它每年引起的病例数量来衡量。尽管英格兰和威尔士的食源性沙门氏菌病例数量目前正在下降，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60万例死亡。这与抗生素耐药性的不断增加的负担相结合，意味着我们必须确定新的疫苗和抗生素靶点，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。使用疫苗从食物链中清除沙门氏菌的成功可以通过鸡的疫苗接种来衡量-通过超市鸡蛋上的狮子标记来表示。这就是上述沙门氏菌食物中毒下降的原因。英国猪群是鼠伤寒沙门氏菌的巨大储存库，23%的GB猪携带沙门氏菌-它们目前没有接种疫苗。猪肉是欧洲消费量最大的肉类，与猪肉相关的沙门氏菌食物中毒正在增加。猪中的沙门氏菌需要根除。我们已经确定了沙门氏菌的RpoE和CpxRA包膜应激反应途径的成员，这些途径已显示出作为疫苗靶点的前景。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，使优秀的药物靶点。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，我们可以真正推动信封！

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!