IMPACT OF FUNGAL ADAPTATION UPON HOST RECOGNITION AND PATHOGENESIS

真菌适应对宿主识别和发病机制的影响

• 批准号: MR/M026663/1
• 负责人: Al Brown
• 金额: $ 252.47万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM026663%2F1
• 关键词: IMPACT; FUNGAL; ADAPTATION; UPON; HOST

Fungal infections have a major impact on human health. Pathogenic (disease causing) fungi cause life-changing oral, genital and skin infections, and life-threatening systemic infections affecting internal organs. Most individuals carry the fungus Candida albicans in their microflora. Normally our immune system recognises invading Candida cells and kills them, thereby protecting us from infection. However, Candida infections arise when the efficiency of this immune surveillance is compromised. Hence this fungus is a frequent cause of irritating yeast infections such as "thrush". It also causes life-threatening bloodstream infections in weak and vulnerable patients, often undoing the excellent work done by cancer treatment and intensive care medicine. Indeed, in some patient groups, over 40% of these infections are fatal. As well as having a significant impact on human health, these infections have a significant economic impact. Despite the availability of reasonably effective antifungal drugs, bloodstream infections are estimated to extend the hospitalisation of patients by 22 days, increasing health care costs by over £20,000 per patient. As yet, no antifungal vaccines are available. Their development depends on an understanding of the mechanisms by which our immune system recognises and kills Candida cells.Significant progress has been made however. Research from a number of laboratories (including our own) has revealed that immune cells recognise specific types of molecule on the Candida cell surface as "foreign". After recognising these molecules ("pathogen-associated molecular patterns"), the immune cells generally swallow the Candida cells (a process called "phagocytosis"), and then kill them by subjecting the fungus to a battery of toxic chemicals, thereby clearing the infection. This generally accepted view is based largely on experiments involving Candida albicans cells grown in the laboratory under well-defined culture conditions on specific growth media, and not cells grown in an infected host. Unfortunately, these laboratory growth media differ significantly from the conditions that Candida experiences during an infection. We have shown recently that changes in growth conditions significantly affect: (a) the architecture of the Candida cell surface; (b) recognition by our immune system; and (c) Candida's capacity to cause disease. Therefore our hypothesis is that during the onset and progression of an infection, Candida cells encounter and adapt to changes in host niches, thereby affecting their growth. This affects the expression and exposure of "pathogen-associated molecular patterns" on the fungal cell surface. We predict that these changes strongly influence the effectiveness of local immune surveillance, allowing more fungal cells to survive these host defences, thereby influencing disease progression and the outcome of the infection. In other words, fungal physiology resists host immunology. The over-arching goal of our research programme is to test this hypothesis by defining the effects of Candida adaptation mechanisms upon the efficacy of immune surveillance and infection outcome. With the help of the three postdoctoral researchers, plus two PhD students provided by Aberdeen University, we will achieve this by combining our synergistic expertise in the analysis of Candida albicans nutrient and stress adaptation, the Candida cell surface, Candida pathogen-associated molecular patterns and immune recognition, the dynamics of phagocytosis and fungal killing, and Candida infection biology. We will integrate well-established molecular approaches with powerful new genomic technologies and state-of-the-art cellular imaging (many of which were developed in our labs). This research is essential if we are to properly understand anti-Candida immunity in the context of disease onset and progression. This knowledge will facilitate the development of effective anti-Candida vaccines and novel immunotherapies.

真菌感染对人类健康有重大影响。致病真菌会导致改变生命的口腔、生殖器和皮肤感染，以及影响内脏器官的危及生命的全身感染。大多数人在他们的微生物区系中携带真菌白色念珠菌。通常我们的免疫系统会识别入侵的念珠菌细胞并杀死它们，从而保护我们免受感染。然而，当这种免疫监视的效率受到损害时，念珠菌感染就会出现。因此，这种真菌是刺激性酵母感染，如“鹅口疮”的常见原因。它还导致虚弱和脆弱患者发生危及生命的血液感染，通常会破坏癌症治疗和重症监护医学所做的出色工作。事实上，在一些患者群体中，超过40%的这些感染是致命的。除了对人类健康产生重大影响外，这些感染还产生重大的经济影响。尽管有相当有效的抗真菌药物，但据估计，血流感染会使患者的住院时间延长22天，使每位患者的医疗保健费用增加20，000英镑以上。到目前为止，还没有抗真菌疫苗。它们的发展依赖于对我们的免疫系统识别和杀死念珠菌细胞的机制的理解。然而，已经取得了重大进展。许多实验室（包括我们自己的实验室）的研究表明，免疫细胞将念珠菌细胞表面上的特定类型的分子识别为“外来”。在识别这些分子（“病原体相关分子模式”）后，免疫细胞通常会吞噬念珠菌细胞（一个称为“吞噬作用”的过程），然后通过使真菌接触一系列有毒化学物质来杀死它们，从而清除感染。这种普遍接受的观点主要是基于实验室中在特定生长培养基上的明确培养条件下生长的白色念珠菌细胞，而不是在感染宿主中生长的细胞。不幸的是，这些实验室生长培养基与念珠菌在感染期间经历的条件显著不同。我们最近已经表明，生长条件的变化显著影响：（a）念珠菌细胞表面的结构;（B）我们的免疫系统的识别;和（c）念珠菌引起疾病的能力。因此，我们的假设是，在感染的发生和发展过程中，念珠菌细胞遇到并适应宿主生态位的变化，从而影响其生长。这会影响真菌细胞表面上“病原体相关分子模式”的表达和暴露。我们预测这些变化强烈影响局部免疫监视的有效性，使更多的真菌细胞在这些宿主防御中存活，从而影响疾病进展和感染的结果。换句话说，真菌生理学抵抗宿主免疫学。我们的研究计划的首要目标是通过确定念珠菌适应机制对免疫监视和感染结果的影响来验证这一假设。在三名博士后研究人员以及阿伯丁大学提供的两名博士生的帮助下，我们将通过结合我们在白色念珠菌营养和压力适应分析，念珠菌细胞表面，念珠菌病原体相关分子模式和免疫识别，吞噬和真菌杀伤动力学以及念珠菌感染生物学方面的协同专业知识来实现这一目标。我们将整合成熟的分子方法与强大的新基因组技术和最先进的细胞成像（其中许多是在我们的实验室开发的）。这项研究是必不可少的，如果我们要正确理解抗念珠菌免疫的背景下，疾病的发病和进展。这些知识将有助于开发有效的抗念珠菌疫苗和新型免疫疗法。

项目成果

In-host microevolution of Aspergillus fumigatus: A phenotypic and genotypic analysis.

• DOI: 10.1016/j.fgb.2018.02.003
• 发表时间: 2018-04
• 期刊: Fungal genetics and biology : FG & B
• 作者: Ballard E;Melchers WJG;Zoll J;Brown AJP;Verweij PE;Warris A
• 通讯作者: Warris A

The Third International Symposium on Fungal Stress - ISFUS.

• DOI: 10.1016/j.funbio.2020.02.007
• 发表时间: 2017-11
• 期刊: Fungal biology
• 影响因子: 2.5
• 作者: Alene Alder-Rangel;A. Idnurm;A. Brand;A. J. Brown;A. Gorbushina;Christina M. Kelliher;C. B. Campos;D. E. Levin;D. Bell-Pedersen;E. Dadachova;F. Bauer;G. Gadd;G. Braus;G. U. Braga;G. Brancini;G. Walker;Irina S Druzhinina;I. Pócsi;J. Dijksterhuis;J. Aguirre;J. E. Hallsworth;J. Schumacher;K. H. Wong;L. Selbmann;L. Corrochano;M. Kupiec;M. Momany;M. Molin;N. Requena;O. Yarden;Radames J. B. Cordero;R. Fischer;R. Pascon;R. Mancinelli;T. Emri;T. O. Basso;D. Rangel

Immune cells fold and damage fungal hyphae.

• DOI: 10.1073/pnas.2020484118
• 发表时间: 2021-04-13
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Bain JM;Alonso MF;Childers DS;Walls CA;Mackenzie K;Pradhan A;Lewis LE;Louw J;Avelar GM;Larcombe DE;Netea MG;Gow NAR;Brown GD;Erwig LP;Brown AJP
• 通讯作者: Brown AJP

Fungal spore swelling and germination are restricted by the macrophage phagolysosome

真菌孢子的膨胀和萌发受到巨噬细胞吞噬溶酶体的限制

• DOI: 10.1016/j.funbio.2023.08.002
• 发表时间: 2023
• 期刊: Fungal Biology
• 影响因子: 2.5
• 作者: Alonso M

The nature of the fungal cargo induces significantly different temporal programmes of macrophage phagocytosis.

• DOI: 10.1016/j.tcsw.2022.100082
• 发表时间: 2022-12
• 期刊: Cell surface (Amsterdam, Netherlands)
• 作者: Alonso, Maria Fernanda;Bain, Judith M.;Rudkin, Fiona M.;Erwig, Lars P.;Brown, Alistair J. P.;Gow, Neil A. R.
• 通讯作者: Gow, Neil A. R.