Combatting resistance to combinatorial stress and macrophage killing in Candida glabrata.

对抗光滑念珠菌对组合应激和巨噬细胞杀伤的抵抗力。

• 批准号: BB/W009625/1
• 负责人: Jane Usher
• 金额: $ 51.67万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW009625%2F1
• 关键词: Combatting; resistance; combinatorial; stress; macrophage

The processes of life are dynamic and it is change on a molecular level that enables organisms to grow but to also adapt to and survive in different environments, such as the ability to cause disease within a human host. My research focuses on the human fungal pathogen, Candida glabrata, which can cause illness in humans ranging from allergic reactions, infections such as thrush which affects ~75% of women at least once, to serious disease in patients that have impaired immune systems. These fungi are increasing in incidence and the reason for this increase is not understood. However, it is clear that the fungus can defend itself against high levels of stress and antifungal drugs used in treatment regimes. My hypothesis is that C. glabrata has evolved the capabilities to withstand a challenge from the combination of environmental and imposed drug stresses.Firstly, to look at C. glabrata, I will take advantage of my recent discovery of the sexual cycle in this fungus which offers novel methods to test hypotheses about evolution and pathogenesis. Pathogens of humans (microbes that can cause infection), such as C. glabrata, are successful because they adapt effectively to environmental stresses encountered within the host body. Upon recognition by host immune cells, C. glabrata is engulfed and exposed to a combination of stresses. In contrast to other pathogenic fungi, C. glabrata is highly resistant to stress allowing it to survive the host immune defences. This suggests that resistance to both antifungal drugs (a stress brought on by medical intervention) and natural host-induced stresses are essential for establishment and progression of infection. The molecular mechanisms underpinning antifungal resistance and the response to individual stresses, have been investigated in isolation, however little is known about how C. glabrata adapts to combinatorial stresses. The mechanistic explanation of stress adaptation will yield new insights into Candida infection. Using my newly discovered sexual cycle in C. glabrata, I have generated a series of related strains of the same fungal pathogen that have increased resistance to combinatorial and drug stresses. I will sequence their genomes (a process for analysing DNA) to identify the critical genes involved in stress resistance and characterise the mechanisms of C. glabrata stress responses. My preliminary data and publications demonstrate that the C. glabrata response to in vitro (performed in the lab outside of the human body) combinatorial stress is similar to that observed upon phagocyte engulfment (when immune cells recognise pathogens and try to remove them). At the level of gene expression, there is an up-regulation of genes (the process by which information encoded in a gene is used to make more proteins) encoding functions related to stress adaptation and nutrient recycling overlap. Understanding this regulatory network and the role that selected components (different genes) play in stress resistance, is essential to the development of future drug regimes.

生命的过程是动态的，是分子水平上的变化使生物体能够生长，但也能适应并在不同的环境中生存，例如在人类宿主中引起疾病的能力。我的研究重点是人类真菌病原体，光滑念珠菌，它可以引起人类疾病，从过敏反应，感染，如鹅口疮，影响~75%的妇女至少一次，严重的疾病，患者免疫系统受损。这些真菌的发病率正在增加，其原因尚不清楚。然而，很明显，真菌可以保护自己免受高水平的压力和治疗方案中使用的抗真菌药物。我的假设是C. glabrata已经进化出了抵抗环境和药物胁迫的能力。glabrata，我将利用我最近发现的性周期在这种真菌提供了新的方法来测试有关进化和发病机制的假设。人类的病原体（可引起感染的微生物），如C。glabrata是成功的，因为它们有效地适应了宿主体内遇到的环境压力。一旦被宿主免疫细胞识别，C. glabrata被吞没并暴露于应力的组合。与其他病原真菌相比，C. glabrata对压力具有高度抗性，使其能够在宿主免疫防御中存活。这表明，抗真菌药物的耐药性（由医疗干预带来的压力）和自然宿主诱导的压力对于感染的建立和进展至关重要。抗真菌耐药的分子机制和对个体胁迫的反应已经被单独研究，但是对C。glabrata适应组合应力。压力适应的机制解释将产生新的见解念珠菌感染。利用我新发现的性周期。glabrata，我已经产生了一系列相同真菌病原体的相关菌株，这些菌株对组合和药物胁迫的抗性增加。我将对它们的基因组进行测序（一种分析DNA的过程），以确定与抗逆有关的关键基因，并阐明C。glabrata应激反应。我的初步数据和出版物表明，C。glabrata对体外（在人体外的实验室中进行）组合应激的反应类似于在吞噬细胞吞噬（当免疫细胞识别病原体并试图去除它们时）时观察到的反应。在基因表达水平上，有一个基因的上调（基因中编码的信息被用来制造更多蛋白质的过程），编码与压力适应和营养循环重叠相关的功能。了解这种调控网络和所选成分（不同基因）在抗应激中的作用，对于未来药物方案的开发至关重要。

项目成果

Zinc prevents vaginal candidiasis by inhibiting expression of an inflammatory fungal protein

• DOI: 10.1126/scitranslmed.adi3363
• 发表时间: 2023-12-06
• 期刊: SCIENCE TRANSLATIONAL MEDICINE
• 影响因子: 17.1
• 作者: Roselletti，Elena;Pericolini，Eva;Wilson，Duncan
• 通讯作者: Wilson，Duncan

Is There a Relationship Between Mating and Pathogenesis in Two Human Fungal Pathogens, Candida albicans and Candida glabrata?

• DOI: 10.1007/s40588-023-00192-8
• 发表时间: 2023
• 期刊: CURRENT CLINICAL MICROBIOLOGY REPORTS
• 影响因子: 5.2
• 作者: Bedekovic, Tina;Usher, Jane
• 通讯作者: Usher, Jane

The Candida glabrata Parent Strain Trap: How Phenotypic Diversity Affects Metabolic Fitness and Host Interactions.

• DOI: 10.1128/spectrum.03724-22
• 发表时间: 2023-02-14
• 期刊: Microbiology spectrum
• 影响因子: 3.7

Candida glabrata: A powerhouse of resistance.

• DOI: 10.1371/journal.ppat.1011651
• 发表时间: 2023-10
• 期刊: PLoS pathogens
• 影响因子: 6.7