Combinatorial responses of fungal pathogens to their human hosts: an Integrative Systems Biology approach

真菌病原体对其人类宿主的组合反应：综合系统生物学方法

• 批准号: BB/F00513X/1
• 负责人: Al Brown
• 金额: $ 320.48万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF00513X%2F1
• 关键词: Combinatorial; responses; fungal; pathogens; their

Biological systems are constantly subjected to a wide variety of external stimuli and challenges. Many of these change continuously and in order to survive the organism must respond appropriately to each new set of circumstances. It is however difficult for scientists to study such complex perturbations and so typically researchers have focused on one stimulus at a time. Whilst this has yielded major biological insights, to make further progress we need to develop approaches to studying combinations of several simultaneous perturbations. This cannot be done using conventional experimental techniques alone. These need to be supplemented by mathematical and computational modelling methods, which can integrate data from different experiments, reveal hidden patterns, explain apparently contradictory results and suggest new biological hypotheses. This type of interdisciplinary research is called Systems Biology. Recently a number of centres have been established in the UK to champion Integrative Systems Biology. This project involves one of these centres (CISBIC) at Imperial College London, whose focus is on the interaction between pathogens and their hosts. CISBIC will be partnered by Aberdeen University, thereby extending the range of pathogens studied at CISBIC, strengthening the two institutions existing collaborations and helping to integrate the rapidly growing systems biology group at Aberdeen into the UK and European community. We intend to apply Integrative Systems Biology techniques to understanding how pathogenic fungi respond to the combinations of different stresses they encounter when they invade a human host. We shall focus on the major fungal pathogens of humans, Candida albicans and Candida glabrata. They cause frequent oral and vaginal infections (thrush) and cause life-threatening infections of the bloodstream and internal organs in transplant and cancer patients. When such pathogens invade a patient, the immune system normally responds with a variety of counter-measures designed to kill the pathogen. For the microbe these counter-measures are essentially equivalent to environmental stresses, and hence it activates strategies to minimize the damage done by these stresses. The success of the pathogen depends on how well it counteracts these stresses to defeat the host's defences. We will study how these pathogenic Candida species respond to the combinations of stresses they experience in their human host. We will start by investigating each of three stresses in isolation and then use a mixture of experiments and models to explore how these responses differ when two different stresses are applied together. We will then use this information to predict and then validate what happens when the three stresses are encountered simultaneously. Finally, we will evaluate the extent to which our understanding of stress responses in these two pathogenic species can be used to predict the responses of related species for which less experimental information is available. This is an important biological question / this project will provide invaluable information about how biological systems in general respond to combinations of environmental signals as well as increasing our understanding of how pathogenic microbes interact with humans.

生物系统不断受到各种各样的外部刺激和挑战。其中许多是不断变化的，为了生存，有机体必须对每一组新的环境做出适当的反应。然而，科学家很难研究如此复杂的扰动，因此研究人员通常一次只关注一种刺激。虽然这已经产生了重大的生物学见解，取得进一步的进展，我们需要开发的方法来研究几个同时扰动的组合。这不能单独使用传统的实验技术。这些需要辅以数学和计算建模方法，这些方法可以整合来自不同实验的数据，揭示隐藏的模式，解释明显矛盾的结果，并提出新的生物学假设。这种跨学科的研究被称为系统生物学。最近在英国建立了一些中心来支持综合系统生物学。该项目涉及伦敦帝国学院的一个中心（CISBIC），其重点是病原体与其宿主之间的相互作用。CISBIC将与阿伯丁大学合作，从而扩大CISBIC研究的病原体范围，加强两个机构现有的合作，并帮助阿伯丁快速发展的系统生物学小组融入英国和欧洲共同体。我们打算应用综合系统生物学技术来了解病原真菌如何应对它们入侵人类宿主时遇到的不同压力的组合。我们将集中在人类的主要真菌病原体，白色念珠菌和光滑念珠菌。它们会引起频繁的口腔和阴道感染（鹅口疮），并在移植和癌症患者中引起危及生命的血流和内脏感染。当这些病原体侵入患者时，免疫系统通常会采取各种旨在杀死病原体的对抗措施。对于微生物来说，这些应对措施基本上等同于环境压力，因此它激活策略以最大限度地减少这些压力造成的损害。病原体的成功取决于它如何抵消这些压力，以击败宿主的防御。我们将研究这些致病性念珠菌如何应对它们在人类宿主中经历的压力组合。我们将从单独研究三种压力中的每一种开始，然后使用实验和模型的混合来探索当两种不同的压力一起施加时，这些反应如何不同。然后，我们将使用这些信息来预测并验证当三种应力同时遇到时会发生什么。最后，我们将评估我们对这两种致病物种的应激反应的理解在多大程度上可以用来预测相关物种的反应，这些物种的实验信息较少。这是一个重要的生物学问题/该项目将提供有关生物系统如何对环境信号组合做出反应的宝贵信息，并增加我们对病原微生物如何与人类相互作用的理解。

项目成果

Gross karyotypic and phenotypic alterations among different progenies of the Candida glabrata CBS138/ATCC2001 reference strain.

• DOI: 10.1371/journal.pone.0052218
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bader O;Schwarz A;Kraneveld EA;Tangwattanachuleeporn M;Schmidt P;Jacobsen MD;Gross U;De Groot PW;Weig M
• 通讯作者: Weig M

Microbial signaling and systems biology.

微生物信号传导和系统生物学。

• DOI: 10.1186/gb-2010-11-5-302
• 发表时间: 2010
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Brown AJ

Limited resources in a driven diffusion process.

• DOI: 10.1103/physrevlett.105.078102
• 发表时间: 2010-08-13
• 期刊: Physical review letters
• 影响因子: 8.6
• 作者: Brackley CA;Romano MC;Grebogi C;Thiel M
• 通讯作者: Thiel M

Drug-mediated metabolic tipping between antibiotic resistant states in a mixed-species community.

• DOI: 10.1038/s41559-018-0582-7
• 发表时间: 2018-08
• 期刊: Nature ecology & evolution
• 影响因子: 16.8
• 作者: Beardmore RE;Cook E;Nilsson S;Smith AR;Tillmann A;Esquivel BD;Haynes K;Gow NAR;Brown AJP;White TC;Gudelj I
• 通讯作者: Gudelj I

Author Correction: Drug-mediated metabolic tipping between antibiotic resistant states in a mixed-species community.

作者更正：混合物种群落中抗生素耐药状态之间药物介导的代谢倾斜。

• DOI: 10.1038/s41559-018-0678-0
• 发表时间: 2018
• 期刊: Nature ecology & evolution
• 影响因子: 16.8
• 作者: Beardmore RE