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

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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.