FUNGAL NEIGHBOURHOOD WATCH: UNDERSTANDING HOW COMBINATORIAL SIGNALS FROM THE HOST NICHE DRIVE PATHOGENESIS IN CANDIDA ALBICANS

真菌王国估计包含150万种，目前仅描述了70，000种。这些物种中的许多对植物和动物是致病的。大多数感染人类的真菌被归类为机会致病菌，因为它们很少在健康个体中引起疾病，而是“靶向”免疫抑制患者。免疫抑制疗法的使用增加和人口老龄化的增加，以及抗真菌耐药菌株的发展和诊断技术的不足，导致多年来真菌感染急剧上升。因此，迫切需要开发新的真菌诊断和抗真菌疗法。真菌能够定殖并随后感染许多不同的人体部位，包括皮肤、指甲、肺、脑、器官和口腔、生殖器和胃肠道。这些地点中的每一个都有其自身的环境特征和局部防御机制，真菌必须能够适应和抵抗，以保持其在生态位中的地位。目前，我们只知道这些环境是什么，它们是如何被感知的，以及真菌如何利用这些环境信号来推动疾病进展。然而，我们所知道的是，从体外研究解剖单一信号的反应，是许多宿主来源的信号，包括血清，pH值和温度驱动真菌的毒力，而微生物来源的信号抑制这些特征。在生态位中，真菌病原体将同时暴露于宿主和微生物来源的信号。因此，了解这种对立性状的双重反应是如何协调的，是宿主-病原体相互作用领域的一个重要目标。除了影响真菌发病机制的环境外，不同的环境可能会影响我们的免疫系统如何看待病原体。真菌被多层细胞壁包围，作为抵御环境和宿主免疫防御的保护屏障。细胞壁是高度动态的结构，其组成取决于局部环境。细胞壁的外层是由糖高度修饰的蛋白质形成的。这些糖被白色血细胞表面的特异性受体识别，这些受体被称为吞噬细胞，是宿主免疫系统的一部分。在识别后，真菌被吞噬细胞吞噬并杀死。因此，由于环境信号，真菌细胞壁的变化将影响吞噬细胞识别并随后杀死病原体的能力。我们对环境感知的大部分理解来自使用高浓度隔离信号的体外研究，没有试图解决真菌如何感知它在宿主生态位中遇到的多因子信号。我的目标是解决这个根本的差距，在我们的知识，宿主-病原体相互作用，使用一个主要的人类真菌病原体，白色念珠菌，作为真菌感染的模型。我的应用程序将使用基本的病原体细胞生物学，以了解C。白色念珠菌在不同的主机壁龛。具体来说，我将讨论这种成功的机会性真菌病原体如何感知感染过程中遇到的多种环境信号，这些组合环境如何影响真菌，以及真菌如何利用这些环境来隐藏和逃避我们的免疫系统。了解C.白念珠菌和宿主环境的研究为改进诊断工具和发现新型抗真菌疗法的靶点开辟了可能性。

The fungal kingdom is estimated to contain 1.5 million species with only 70,000 species currently described. Many of these species are pathogenic to plants and animals. Most fungi that infect humans are classed as opportunistic pathogens because they seldom cause disease in healthy individuals, but "target" immune suppressed patients. The increased use of immune suppression therapies and an increasing aging population, together with the development of antifungal resistant isolates and inadequate diagnostic techniques has led to a dramatic rise in fungal infections over the years. Therefore, there is urgent need for the development of new fungal diagnostics and anti-fungal therapies. Fungi are capable of colonising and subsequently infecting many different human body sites including the skin, nails, lungs, brain, organs and oral, genital and gastrointestinal tracts. Each of these sites has its own environmental characteristics and local defence mechanisms to which the fungus must be able to adapt to, and resist, in order to maintain its position in the niche. Currently, we only have basic knowledge of what these environments are, how they are sensed, and how the fungus uses these environmental signals to drive disease progression. However, what we do know, from in vitro studies dissecting the response of single signals, is that many host-derived signals including serum, pH and temperature drive fungal virulence, while microbe-derived signals dampen these characteristics. In the niche, the fungal pathogen will be simultaneously exposed to both host and microbe-derived signals. Therefore, understanding how the dual response to such opposing traits is orchestrated is an essential goal for the host-pathogen interaction field. In addition to environments affecting fungal pathogenesis, different environments are likely to impact on how our immune system sees the pathogen. Fungi are surrounded by a multi-layered cell wall, which serves as a protective shield against the environment and host immune defences. The cell wall is a highly dynamic structure and its composition is dependent on the local environment. The outer layer of the cell wall is formed from proteins that are highly decorated with sugars. These sugars are recognised by specific receptors on the surface of white blood cells, called phagocytes, which form part of the host's immune system. After recognition, the fungus is engulfed and killed by the phagocyte. Therefore, changes in the fungal cell wall, due to environmental signals, will affect the ability of the phagocyte to recognise and subsequently kill the pathogen. The majority of our understanding of environmental sensing, comes from in vitro studies using isolated signals at high concentrations, with no attempt to address how the fungus perceives the multifactorial signals it will encounter in the host niche. I aim to address this fundamental gap in our knowledge of host-pathogen interactions by using one of the major human fungal pathogens, Candida albicans, as a model for fungal infection. My application will use fundamental pathogen cell biology in order to understand the behaviour of C. albicans in diverse host niches. Specifically, I will address how this successful opportunistic fungal pathogen perceives multiple environmental signals encountered during infection, how these combinatorial environments affect the fungus, and how in turn the fungus uses these environments to hide and escape from our immune system. Understanding the effects of the interactions between C. albicans and the host environment opens up the potential to improve diagnostic tools and discover targets for novel anti-fungal therapies.