De-cloaking the cell wall: investigating the molecular mechanism(s) of cell wall remodelling during adaptation to environmental pH in Candida albicans

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The development of new antifungals is slower than antibacterials as fungi are eukaryotes and are therefore very similar to humans. However, the sugar structures that make up the cell wall are specific to fungi and are made by fungal specific enzymes. Therefore, the pathways that synthesise the cell wall are excellent targets for the development of new antifungal agents. However, at the moment we have little information on how the production of the cell wall is regulated, and how the cell wall changes upon contact with the human host. A deeper understanding of these processes will enable us to develop better antifungals and diagnostics in the future.All fungi are surrounded by a thick exterior cell wall, comprised of sugars. The fungal cell wall is essential for maintaining the shape of the fungus, and for fungal survival, by providing a protective barrier from the external environment. The cell wall is also the key fungal component that is recognised as foreign material by our immune system, initiating clearance from infected sites. Therefore, this sugary coat plays many important roles during fungal infection.The sugars that comprise the fungal cell wall are chitin, glucan and proteins decorated with sugars called mannoproteins. These sugars are assembled in a particular fashion so that the chitin and glucan are closest to the fungal cell, and provide the rigidity of the fungal cell, with the mannoproteins forming the outermost hair-like layer, that enables the fungus to stick to surfaces and other cells. Candida albicans is the fungal pathogen most often associated with genital thrush. Almost all women will experience at least one episode of thrush in their lifetime; while up to 15% will experience multiple infections. Although not life-threatening these infections are painful and have a significant affect on the well-being of women. In this infection, the fungus has to survive in the acidic environment of the female reproductive tract. We have shown that low environmental pH affects the structural organisation of the fungal cell wall. This change in the fungal cell wall results in over stimulation of the immune system, resulting in the symptoms associated with thrush. We now want to know how fungi mediate these changes in their cell wall in response to the low pH of the female reproductive tract, and whether these modifications are required for survival of the fungus in this environment. Addressing these questions will enable us to develop better anti-fungal drugs in the future and provide a rationale as to why some women experience more painful or recurrent infections, and this information will inform measures to improve women's health and well-being.