MICA: Study of disease mechanisms in enteric fever to characterise innate & adaptive immunity in mucosa & blood in controlled human infection model

伤寒（也称为肠热病）是一种以腹泻和皮疹为特征的感染，通常由一种称为肠道沙门氏菌的细菌引起。在通过受污染的食物或饮料进入人体后，沙门氏菌首先进入肠道，然后进入血液，从那里它们可以感染淋巴结，胆囊，肝脏，脾脏和身体的其他部位。肠热病的治疗是通过静脉补液或饮用未污染的水与电解质混合。抗生素被用来杀死细菌，但随着抗生素耐药性S。在世界范围内，这种治疗方法越来越不有效。两种沙门氏菌变种，称为血清型伤寒和副伤寒，每年在全世界造成约2700万例肠热病和20多万例死亡，其中大部分发生在发展中国家。尽管通过经济发展改善卫生条件最终将消除肠热病，但通过有效的免疫接种，特别是在抗生素耐药性日益增加的情况下，可以在中期内减少疾病负担。尽管在不久的将来可能会有有效的疫苗用于大规模接种伤寒疫苗，但这些疫苗仅对那些S菌株有效。伤寒和沙门氏菌。携带Vi多糖荚膜蛋白的副伤寒。没有这些荚膜蛋白或没有荚膜（无荚膜）的菌株将不受疫苗接种的影响，并可能填补被荚膜菌株空出的生态空间。事实上，由S.甲型副伤寒不携带Vi蛋白，目前没有疫苗，在过去十年中有所上升，在一些地区占所有病例的一半以上。因此，重要的是，有效的疫苗可用于保护免受胶囊化和非胶囊化肠道沙门氏菌的感染。为了开发这样的疫苗，我们需要充分了解人类对无囊沙门氏菌的免疫反应，包括内在免疫系统和疾病特异性免疫之间的相互作用，肠道和血液中免疫的贡献，对蛋白质和多糖决定簇的免疫反应，以及抗体的作用。在自然感染或接种疫苗后，胶囊和非胶囊伤寒沙门氏菌之间有多少交叉保护尚不清楚，但这对疫苗开发至关重要。通过该项目，我们的目标是填补上述知识空白，充分表征肠道发热的感染过程和免疫反应。

Typhoid fever (also known as enteric fever), an infection characterised by diarrhoea and rash, is most often caused by a type of bacteria called Salmonella enterica. After gaining entry to the body via contaminated food or drink, the Salmonellae travel first to the gut, and then the bloodstream, from where they can infect the lymph nodes, gallbladder, liver, spleen, and other parts of the body. Treatment of enteric fever is by rehydration either intravenously or by drinking uncontaminated water mixed with electrolytes. Antibiotics are used to kill the bacteria, but as there are increasing rates of antibiotic resistant S. enterica throughout the world, this means of treatment is becoming less effective. Two Salmonella variants, known as serovars Typhi and Paratyphi, cause around 27 million cases of enteric fever and more than 200,000 deaths per year worldwide, mostly in the developing countries. Even though improved sanitation through economic development should eventually eliminate enteric fever, reduction of the disease burden in the medium term is achievable through effective immunisation, especially in the face of increasing antibiotic resistance.Although effective vaccines are likely to be available for mass vaccination against typhoid in the near future, these vaccines will be effective only against those strains of S. Typhi and S. Paratyphi that bear the Vi polysaccaharide capsule proteins. Strains that do not have these capsule proteins, or that have no capsule (acapsulate) will be unaffected by vaccination and could fill the ecological space vacated by the capsulate strains. Indeed, enteric fever caused by S. Paratyphi A which does not carry the Vi protein and for which there is currently no vaccine, has risen during the past decade and accounts for more than half of all cases in some areas. Thus it is important that effective vaccines are available to protect against infection by both capsulated and non-encapsulated Salmonella enterica. To develop such vaccines, we need a full understanding of the human immune response to the acapsulate Salmonella including the interactions between the inbuilt immune system and disease-specific immunity, contributions of immunity in the gut and the bloodstream, immune response to protein and to polysaccharide determinants, and the role of antibodies. How much cross-protection there is between capsulate and non-capsulate typhoidal Salmonellae after natural infection or vaccination is not known, but this is critically important to vaccine development.With this project we aim to fill in the knowledge gaps highlighted above, by fully characterising the infection process and immune response in enteric fever.