Identification of putative pan-streptococcal vaccine targets

假定的泛链球菌疫苗靶标的鉴定

• 批准号: 2595188
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2595188
• 关键词: Identification; putative; pan; streptococcal; vaccine

Streptococci cause significant economic and stock losses in the agriculture, aquaculture and have a serious impact on human health. These key threats from the continued intensification of food production are driven by the growing human:cattle:swine:fish interface and intensification of these livestock sectors. Antibiotic control of disease is becoming less feasible due to growing resistance and the threat of gene transfer within this zoonotic pathogen and alternative control strategies are urgently required. Limited strain, prevalence and sequence information exists for zoonotic Streptococcus and functional characterisation of these strains will provide key virulence related information for potential future control-based strategies. Identification of the key components of bacteria that are involved in the infection process will allow the development of alternative therapies that prevent transmission. Alternately, these components may be incorporated into diagnostic tests to identify those strains naturally carried that are more likely cause infection, allowing a more targeted approach for treatment in those situations where transmission leading to disease is more likely. Either approach would greatly reduce the incidence of streptococcal infection in humans and livestock and thus reduce mortality associated with this disease. This project will characterise genes/proteins essential for pan-streptococcal pathogenesis in humans, fish and cattle using vast archive of random mutagenesis high throughput sequencing data which have been generated in the Streptococcal Research Group (SRG) at SVMS. Individual bacterial mutant pools have be generated for representative strains using the pGh9:ISS1 insertional mutagenesis system, and analysed using the new bespoke laboratory and bioinformatic analysis programme we have developed called PIMMS V2. PIMMS V2 will be used to map insertions within the bacterial genomes and identify conditionally important / essential sequences that will be translated to metabolic pathways and biochemical processes for further comparative analysis. Producing information that describes a pan streptococcal essential genome and/or conditionally important genome and metabolic/ biochemical pathways and processes against which new disease control strategeies could be based.The project will initially complete a pangenome analysis of 8 target streptococcal genomes (Streptococcus uberis, iniae, suis, agalactiae, pneumoniae, garviae and dysgalactiae) and incorporate a complete phenotypic pangenome analysis using the existing PIMMS data available leading to the identification of putative pan-streptococcal targets. Additional characterisation of these targets will take place in the laboratory using mutant banks held by SRG, to assess if the putative targets do infer a growth inhibiting effect. The overall output for the project will be a experimentally confirmed data analysis pipeline which will work with the existing PIMMS pipeline to incorporate multiple datasets, producing targets for future larger grant proposal in vaccine development.

链球菌在农业、水产养殖业造成重大经济和种群损失，对人类健康产生严重影响。粮食生产持续集约化带来的这些主要威胁是由不断增长的人：牛：猪：鱼相互作用以及这些畜牧业的集约化所驱动的。由于这种人畜共患病原体的耐药性不断增强以及基因转移的威胁，用抗生素控制疾病变得越来越不可行，迫切需要替代控制策略。人畜共患病链球菌的菌株、流行率和序列信息有限，这些菌株的功能特征将为未来潜在的基于控制的策略提供关键的毒力相关信息。鉴定参与感染过程的细菌的关键成分将有助于开发预防传播的替代疗法。或者，这些成分可以纳入诊断测试中，以识别那些更可能引起感染的自然携带菌株，从而在更有可能传播导致疾病的情况下采用更有针对性的治疗方法。这两种方法都将大大降低人类和牲畜链球菌感染的发病率，从而降低与这种疾病相关的死亡率。该项目将利用 SVMS 链球菌研究组 (SRG) 生成的大量随机诱变高通量测序数据来表征人类、鱼类和牛的泛链球菌发病机制所必需的基因/蛋白质。使用 pGh9:ISS1 插入诱变系统为代表性菌株生成了单个细菌突变体库，并使用我们开发的称为 PIMMS V2 的新定制实验室和生物信息分析程序进行了分析。 PIMMS V2 将用于绘制细菌基因组内的插入图谱，并识别有条件的重要/必需序列，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。产生描述泛链球菌必需基因组和/或有条件重要的基因组以及代谢/生化途径和过程的信息，新的疾病控制策略可以以此为基础。该项目将首先完成 8 个目标链球菌基因组（乳房链球菌、猪链球菌、猪链球菌、无乳链球菌、肺炎链球菌、加维亚链球菌和 停乳症），并使用现有的 PIMMS 数据进行完整的表型全基因组分析，从而识别假定的泛链球菌靶点。这些靶标的额外表征将在实验室中使用 SRG 持有的突变体库进行，以评估假定的靶标是否确实具有生长抑制作用。该项目的总体输出将是一个经过实验确认的数据分析管道，它将与现有的 PIMMS 管道一起整合多个数据集，为未来疫苗开发中更大的拨款提案制定目标。