Newton001 Systems Biology of Typhoid Fever

Newton001 伤寒的系统生物学

• 批准号: MR/M02637X/1
• 负责人: Andrew Pollard
• 金额: $ 5.13万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM02637X%2F1
• 关键词: Newton001; Systems; Biology; Typhoid; Fever

Enteric fever caused by Salmonella Typhi and Paratyphi A is wide spread throughout the world. particularly burdensome in South-East Asia, with approximately >22 million new infections resulting in a 1% fatality rate annually. Control of the disease is hindered due to insufficient understanding of disease pathogenesis and immune responses to the infection, inaccurate diagnostic tests and limited efficacy of licensed vaccines. Thus understanding human host-responses to enteric infections is pivotal in developing improved diagnostic tests and vaccines.The Oxford Vaccine Group (OVG) has recently developed a human challenge model for S. Typhi and Paratyphi A. Briefly, human adult volunteers were orally infected with a pathogenic dose of S. Typhi and Paratyphi A and closely monitored the following days until treatment with antibiotics. This model was subsequently used to test vaccine efficacy by vaccinating participants prior to ingestion of the bacteria. The various samples collected provide a rich dataset consisting of clinical and immunological measurements invaluable to understand disease pathogenesis and human molecular responses to infection. Associated with such large datasets and different levels of data (molecular, serological and clinical) is the challenge of analysis and data integration, which we address through using systems biology approaches.Systems biology/vaccinology is an interdisciplinary field that combines systems-wide measurements, networks, and predictive modelling in the context of biology, vaccines and infectious disease. Computational modelling and integration of multiple levels of data (clinical, immunological, and molecular) develops a multi-facetted understanding of disease pathogenesis and biological mechanisms underlying host-responses to infections/vaccination. Particularly important in this context are regulatory mechanisms, which consist of complex networks involving multiple transcriptional and genetic components. Recently, it has become clear that long non-coding RNAs (lncRNAs) play a pivotal role in the regulation of biological processes by a diverse range of mechanisms. Integrative analysis of transcriptional signatures related to expression of lncRNAs allows us to identify molecular events associated with clinical and immunological outcomes.We are aiming to thoroughly integrate these different datasets to fully investigate the intricacy of human host-responses to infections. We believe that this approach is necessary in order to further shed light on the undisputed complexity of the immune system. As these samples are derived from the human host and a uniquely controlled experimental design, the results will likely elucidate important clues as to how the host reacts to enteric infections and how S. Typhi/Paratyphi A potentially modulate the host-response. By partnering with the Computational Systems Biology Lab at the University of Sao Paulo we are combining one of the largest clinical trials groups in Europe with an excellence in vaccine trials with a team of computational biologists leading in the field of systems vaccinology.

由伤寒沙门氏菌和甲型副伤寒引起的肠道热在世界各地广泛传播。在东南亚尤其沉重，每年约有> 2200万新感染，导致1%的死亡率。由于对疾病发病机理和对感染的免疫反应了解不足、诊断测试不准确以及许可疫苗的效力有限，疾病的控制受到阻碍。因此，了解人类宿主对肠道感染的反应是开发改进的诊断测试和疫苗的关键。伤寒和甲型副伤寒简单地说，成年志愿者口服感染致病剂量的S。伤寒和甲型副伤寒，并密切监测以下几天，直到治疗抗生素。该模型随后被用于测试疫苗效力，即在摄入细菌之前给参与者接种疫苗。收集的各种样本提供了丰富的数据集，包括临床和免疫学测量，对于了解疾病发病机制和人类对感染的分子反应非常宝贵。系统生物学/疫苗学是一个跨学科的领域，它结合了生物学、疫苗和传染病背景下的全系统测量、网络和预测建模。计算建模和多层次数据（临床，免疫学和分子）的整合开发了对疾病发病机制和宿主对感染/疫苗接种反应的生物学机制的多方面理解。在这种情况下，特别重要的是调控机制，其中包括复杂的网络，涉及多个转录和遗传组件。近年来，人们逐渐认识到长链非编码RNA（lncRNA）通过多种机制在生物过程的调控中发挥着重要作用。整合分析与lncRNA表达相关的转录特征使我们能够识别与临床和免疫学结果相关的分子事件。我们的目标是彻底整合这些不同的数据集，以充分研究人类宿主对感染反应的复杂性。我们认为，这种方法是必要的，以进一步阐明免疫系统的无可争议的复杂性。由于这些样本来自人类宿主和一个独特的控制实验设计，结果可能会阐明重要的线索，宿主如何反应肠道感染和如何S。伤寒/甲型副伤寒可能调节宿主反应。通过与圣保罗大学的计算系统生物学实验室合作，我们将欧洲最大的临床试验小组之一与疫苗试验的卓越性与系统疫苗学领域领先的计算生物学家团队相结合。

项目成果

Induction of Cell Cycle and NK Cell Responses by Live-Attenuated Oral Vaccines against Typhoid Fever.

• DOI: 10.3389/fimmu.2017.01276
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Blohmke CJ;Hill J;Darton TC;Carvalho-Burger M;Eustace A;Jones C;Schreiber F;Goodier MR;Dougan G;Nakaya HI;Pollard AJ
• 通讯作者: Pollard AJ

Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever.

• DOI: 10.1084/jem.20151025
• 发表时间: 2016-05-30
• 期刊: The Journal of experimental medicine
• 作者: Blohmke CJ;Darton TC;Jones C;Suarez NM;Waddington CS;Angus B;Zhou L;Hill J;Clare S;Kane L;Mukhopadhyay S;Schreiber F;Duque-Correa MA;Wright JC;Roumeliotis TI;Yu L;Choudhary JS;Mejias A;Ramilo O;Shanyinde M;Sztein MB;Kingsley RA;Lockhart S;Levine MM;Lynn DJ;Dougan G;Pollard AJ
• 通讯作者: Pollard AJ