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）是一种以腹泻和皮疹为特征的感染，最常由一种称为肠沙门氏菌的细菌引起。沙门氏菌通过受污染的食物或饮料进入人体后，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。治疗肠热病可通过静脉注射补液或饮用未受污染的混合电解质水。抗生素被用来杀死细菌，但随着世界各地对抗生素耐药的肠链球菌的比例越来越高，这种治疗手段变得越来越不有效。两种沙门氏菌变种，即伤寒和副伤寒血清型，每年在世界范围内造成约2700万例肠热病例和20多万例死亡，主要发生在发展中国家。尽管通过经济发展改善卫生条件应最终消除肠热病，但在中期，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，减少疾病负担是可以实现的。虽然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，但这些疫苗将仅对那些携带Vi多糖胶囊蛋白的伤寒链球菌和副伤寒链球菌菌株有效。没有这些胶囊蛋白的菌株，或者没有胶囊（胶囊）的菌株将不受疫苗接种的影响，并且可以填补被胶囊菌株空出的生态空间。事实上，甲型副伤寒沙门氏菌引起的肠热在过去十年中有所上升，在某些地区占所有病例的一半以上。甲型副伤寒沙门氏菌不携带病毒Vi蛋白，目前也没有疫苗。因此，重要的是提供有效的疫苗，以防止被荚膜和非荚膜沙门氏菌感染。为了开发这种疫苗，我们需要充分了解人类对胶囊沙门氏菌的免疫反应，包括内在免疫系统与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因素的免疫反应，以及抗体的作用。在自然感染或接种疫苗后，荚膜伤寒沙门氏菌和非荚膜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。在这个项目中，我们的目标是通过充分描述肠热病的感染过程和免疫反应来填补上面强调的知识空白。

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.