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

揭开细胞壁的外衣：研究白色念珠菌适应环境 pH 过程中细胞壁重塑的分子机制

• 批准号: BB/R00966X/1
• 负责人: Rebecca Hall
• 金额: $ 58.08万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR00966X%2F1
• 关键词: De; cloaking; cell; wall; investigating

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.

由于真菌是真核生物，因此与人类非常相似，新的抗真菌药物的开发比抗菌药物慢。然而，构成细胞壁的糖结构是真菌特有的，是由真菌特有的酶制造的。因此，合成细胞壁的途径是开发新的抗真菌药物的绝佳目标。然而，目前我们对细胞壁的产生是如何被调节的，以及细胞壁在与人类宿主接触后是如何变化的信息很少。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。所有的真菌都被一层由糖组成的厚厚的细胞壁包围着。真菌细胞壁对维持真菌的形状和真菌的生存至关重要，因为它提供了一个与外界环境隔绝的保护屏障。细胞壁也是关键的真菌成分，被我们的免疫系统识别为外来物质，开始从感染部位清除。因此，这种含糖外衣在真菌感染过程中起着许多重要作用。构成真菌细胞壁的糖是几丁质、葡聚糖和用甘露糖蛋白修饰的蛋白质。这些糖以一种特殊的方式组装，使几丁质和葡聚糖最接近真菌细胞，并提供真菌细胞的刚性，甘露蛋白形成最外层的毛发状层，使真菌能够粘附在表面和其他细胞上。白色念珠菌是最常与生殖器鹅口疮相关的真菌病原体。几乎所有女性一生中都会至少经历一次鹅口疮；而高达15%的人会经历多重感染。这些感染虽然不会危及生命，但会带来痛苦，并对妇女的健康产生重大影响。在这种感染中，真菌必须在女性生殖道的酸性环境中生存。我们已经表明，低环境pH值影响真菌细胞壁的结构组织。真菌细胞壁的这种变化导致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是如何调节细胞壁的这些变化，以应对女性生殖道的低pH值，以及这些变化是否是真菌在这种环境下生存所必需的。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痛苦或复发性感染提供理由，这些信息将为改善妇女健康和福祉的措施提供信息。

项目成果

Remasking of Candida albicans β-Glucan in Response to Environmental pH Is Regulated by Quorum Sensing

• DOI: 10.1128/mbio.02347-19
• 发表时间: 2019-09-01
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Cottier, Fabien;Sherrington, Sarah;Hall, Rebecca A.
• 通讯作者: Hall, Rebecca A.

Dynamic Fungal Cell Wall Architecture in Stress Adaptation and Immune Evasion.

应激适应和免疫逃避中的动态真菌细胞壁结构。

• DOI: 10.1016/j.tim.2018.01.007
• 发表时间: 2018-04
• 期刊: Trends in microbiology
• 影响因子: 15.9
• 作者: Hopke A;Brown AJP;Hall RA;Wheeler RT
• 通讯作者: Wheeler RT

Transcriptional profiling of Pseudomonas aeruginosa mature single- and dual-species biofilms in response to meropenem.

• DOI: 10.1099/mic.0.001271
• 发表时间: 2023-01
• 期刊: MICROBIOLOGY-SGM
• 影响因子: 2.8
• 作者: Alam, Farhana;Blair, Jessica M. A.;Hall, Rebecca A.
• 通讯作者: Hall, Rebecca A.

Immune Sensing of Candida albicans.

• DOI: 10.3390/jof7020119
• 发表时间: 2021-02-06
• 期刊: Journal of fungi (Basel, Switzerland)
• 作者: Bojang E;Ghuman H;Kumwenda P;Hall RA
• 通讯作者: Hall RA

Understanding How Microorganisms Respond to Acid pH Is Central to Their Control and Successful Exploitation.

• DOI: 10.3389/fmicb.2020.556140
• 发表时间: 2020
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Lund PA;De Biase D;Liran O;Scheler O;Mira NP;Cetecioglu Z;Fernández EN;Bover-Cid S;Hall R;Sauer M;O'Byrne C
• 通讯作者: O'Byrne C