Identification of vaccine targets for Streptococcus suis infection in humans and pigs

猪链球菌（S. suis）在生猪生产中造成严重的死亡率和发病率，影响全球商业和小规模养殖业的经济、动物福利和粮食安全，表现为仔猪的脑膜炎、败血症和多发性关节炎以及成年猪的关节疾病。它也是东南亚流行率最高的一种新出现的人畜共患病原体，败血症和脑膜炎是人类常见的临床进展，越南的细菌性脑膜炎病例高达40%。虽然以β -内酰胺类抗生素治疗可以解决疾病，但关于多重耐药菌株的报告正在增加，世界动物卫生组织已将猪链球菌确定为一种重点疾病，疫苗可以显著减少动物中抗菌素的使用，从而减少产生抗菌素耐药性的压力。本研究的总体目的是确定保护性疫苗和诊断试验的成分，以便更有效地控制人类和猪链球菌感染。该项目将结合随机突变和高通量测序，利用我们现有的细菌突变库，利用pGh9:ISS1插入突变系统，表征全血发病机制所必需的基因/蛋白质。以及一个定制的实验室和生物信息学分析程序，称为PIMMS，它可以识别有条件的重要/必要序列，这些序列将被转化为代谢途径和生化过程，以进行进一步的比较分析。将筛选细菌突变体在全猪和人血液中的生存能力，以确定一系列对生存至关重要的基因，从而成为控制感染的直接目标。将使用现有的PCR筛选方法分离几种表面相关基因的敲除个体细菌突变体，并产生用于抗血清生产、免疫反应性和细菌生长抑制测试的重组版本，作为疫苗接种和诊断测试开发的概念验证实验。

Streptococcus suis (S. suis) is responsible for significant mortality and morbidity in pig production, affecting economics, animal welfare and food security within commercial and small scale farming worldwide and manifests as meningitis, septicaemia and polyarthritis in piglets and joint diseases in adult pigs. It is also an emerging zoonotic pathogen with the highest prevalence in Southeast Asia, with septicaemia and meningitis common clinical progressions in humans, with up to 40% of bacterial meningitis cases in Vietnam. Whilst treatment with beta-lactam based antibiotics can resolve disease, reports of multiple drug resistant strains are increasing and the OIE has identified S. suis as a priority disease for which vaccines could significantly reduce the use of antimicrobials in animals and therefore decreasing pressure on generation of antimicrobial resistance. The overall aim of this study is to identify components for protective vaccine and diagnostic test development for more effective disease control of S. suis infection in both humans and pigs. This studentship will characterise genes/proteins essential for pathogenesis in whole blood using a combination of random mutagenesis and high throughput sequencing, using our existing bacterial mutant pools using the pGh9:ISS1 insertional mutagenesis system, and a bespoke laboratory and bioinformatic analysis programme called PIMMS which identifies conditionally important/essential sequences that will be translated to metabolic pathways and biochemical processes for further comparative analysis. Bacterial mutants will be screened for their ability to survive in whole pig and human blood to determine a list of genes are essential for survival and therefore a direct target for control of infection. Knockout individual bacterial mutants of several surface associated genes will be isolated using existing PCR screening methods and recombinant versions generated for antiserum production, immunoreactivity and bacterial growth inhibition testing as proof of concept experiments for vaccination and diagnostic test development.