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

新的抗真菌药物的开发比抗菌药物的开发要慢，因为真菌是真核生物，因此与人类非常相似。然而，构成细胞壁的糖结构是真菌特有的，是由真菌特有的酶组成的。因此，合成细胞壁的途径是开发新的抗真菌药物的极佳靶点。然而，目前我们对细胞壁的产生是如何调节的，以及与人类宿主接触时细胞壁是如何变化的，我们知之甚少。对这些过程的深入了解将使我们能够在未来开发更好的抗真菌药物和诊断方法。所有的真菌都被由糖组成的厚厚的外细胞壁所包围。真菌细胞壁对保持真菌的形状和真菌的生存是必不可少的，因为它提供了一种免受外部环境影响的屏障。细胞壁也是关键的真菌成分，它被我们的免疫系统识别为异物，启动对感染部位的清除。因此，这种糖衣在真菌感染过程中扮演着许多重要的角色。组成真菌细胞壁的糖是几丁质、葡聚糖和装饰有糖的蛋白质，称为甘露糖蛋白。这些糖以特定的方式组装，使甲壳素和葡聚糖最接近真菌细胞，并提供真菌细胞的刚性，甘露糖蛋白形成最外层的毛状层，使真菌能够附着在表面和其他细胞上。白色念珠菌是生殖器鹅口疮最常见的真菌病原体。几乎所有女性在一生中都会经历至少一次鹅口疮；而多达15%的女性会经历多次感染。虽然不会危及生命，但这些感染是痛苦的，并对妇女的福祉有重大影响。在这种感染中，真菌必须在女性生殖道的酸性环境中生存。我们已经证明，低环境pH会影响真菌细胞壁的结构组织。真菌细胞壁的这种变化会导致对免疫系统的过度刺激，导致与鹅口疮相关的症状。我们现在想知道真菌如何调节细胞壁的这些变化，以响应雌性生殖道的低pH，以及这些修改是否是真菌在这种环境中生存所必需的。解决这些问题将使我们能够在未来开发更好的抗真菌药物，并为为什么一些妇女经历更多痛苦或反复感染提供理由，这些信息将为改善妇女健康和福祉的措施提供依据。

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.