Combinatorial Responses of Fungal Pathogens To Their Human Hosts: an Integrative Systems Biology Approach

生物系统不断地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，但为了取得进一步的进展，我们需要开发方法来研究几个同时扰动的组合。单靠传统的实验技术是无法做到这一点的。这些需要得到数学和计算建模方法的补充，这些方法可以整合来自不同实验的数据，揭示隐藏的模式，解释明显相互矛盾的结果，并提出新的生物学假说。这种跨学科的研究被称为系统生物学。最近，英国已经建立了一些中心来支持整合系统生物学。该项目涉及伦敦帝国理工学院的其中一个中心(CSBIC)，其重点是病原体及其宿主之间的相互作用。CisBIC将与阿伯丁大学合作，从而扩大在CisBIC研究的病原体范围，加强两个机构现有的合作，并帮助将阿伯丁快速增长的系统生物学小组整合到英国和欧洲社区。我们打算应用集成系统生物学技术来了解病原真菌在入侵人类宿主时如何对它们所遇到的不同压力的组合做出反应。我们将重点介绍人类的主要真菌病原体，白色念珠菌和光滑念珠菌。它们导致频繁的口腔和阴道感染(鹅口疮)，并对移植和癌症患者的血液和内脏造成危及生命的感染。当这些病原体入侵患者时，免疫系统通常会采取各种应对措施来杀死病原体。对于微生物来说，这些反措施基本上等同于环境压力，因此它启动了将这些压力造成的损害降至最低的策略。病原体的成功取决于它在多大程度上抵消了这些压力，从而击败了宿主的防御。我们将研究这些致病念珠菌物种如何对它们在人类宿主中经历的压力组合做出反应。我们将从单独研究三种压力开始，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，这些响应如何不同。然后，我们将使用这些信息来预测并验证当同时遇到这三种压力时会发生什么。最后，我们将评估我们对这两个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/该项目将提供关于生物系统一般如何对环境信号组合作出反应的宝贵信息，并增加我们对病原微生物如何与人类相互作用的理解。

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.