Biological function of Candida albicans Ece1 and role in host-microbe interactions

白色念珠菌 Ece1 的生物学功能及其在宿主-微生物相互作用中的作用

• 批准号: BB/J016411/1
• 负责人: Julian Naglik
• 金额: $ 53.55万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ016411%2F1
• 关键词: Biological; function; Candida; albicans; Ece1

The mucosal (oral, vaginal, gastrointestinal) epithelium is of immense importance in protecting humans against a multitude of infections as it is the initial tissue encountered by the majority of microbes. In health, this microbial-epithelial encounter results in either quiescence in the case of harmless 'commensal' microbes or activation of immunity in the case of disease-causing 'pathogenic' microbes. When these normal responses are disrupted a plethora of complications arise, which have implications beyond infection as conditions including cancer and autoimmune disease are associated with abnormal interactions between host and microbe. Given the importance of these interactions, epithelial cells possess distinct mechanisms enabling mucosal tissues to distinguish between commensal and pathogenic microbes.The fungus Candida albicans (C.alb) is an example of a microbe that can exist as a commensal in healthy people but becomes a dangerous pathogen causing severe and potentially fatal disease in unhealthy people. Indeed, Candida infections are regularly found to be the third or fourth most common hospital-acquired bloodstream infection, causing death in ~40% of individuals, and are thus a serious burden to healthcare provision. Given that the vast majority of bloodstream C.alb infections are acquired through mucosal surfaces, it is of paramount importance to understand the mechanisms by which C.alb interacts with epithelial tissues in health and to identify the fungal factors that promote infection and disease when normal responses are disrupted. Presently, we have little knowledge of the fungal factors that promote mucosal infections.Our recent work has been instrumental in understanding the mechanisms by which epithelial cells identify disease-causing C.alb and how this results in immune protection. We previously showed that C.alb infection leads to the secretion of immune activators (cytokines and chemokines) that recruit specific immune cells that protect against C.alb infection. Recently, we found that to activate this protective immune process epithelial cells recognise a specific protein (CaEce1p) on the filamentous, 'invasive' form of C.alb known as hyphae. CaEce1p is a unique hyphal protein consisting of eight repeated fragments of the same size that are individually processed by the enzyme CaKex2p. We provide strong evidence demonstrating that CaEce1p (or its individual fragments) is the critical fungal protein that informs the healthy host of the presence of a microbe that has become dangerous. This proposal aims to demonstrate the function of CaEce1p for C.alb, how CaEce1p is localised to the hyphal surface and, crucially, which fragments of CaEce1p activate epithelial cells. This will provide essential new understanding to basic fungal biology and the mechanisms that underpin C.alb-host interactions in health.This project will identify CaEce1p as a new target not only for the development of new antifungal drugs but also for the development of new vaccines, adjuvants, diagnostic tests and biomarkers for fungal infections. Of additional interest is the structural similarity between CaEce1p and the hypha-specific Rep1 protein of Ustilago maydis, which is a pathogenic plant fungus that causes smut disease in corn. Thus, the functional data obtained with CaEce1p may also provide valuable groundwork for future studies investigating plant fungal pathogenesis.

粘膜（口腔、阴道、胃肠道）上皮在保护人类免受多种感染方面具有巨大的重要性，因为它是大多数微生物遇到的初始组织。在健康的情况下，这种微生物-上皮的接触导致无害的“肠道”微生物的静止或致病的“致病”微生物的免疫激活。当这些正常反应被破坏时，就会出现大量并发症，这些并发症的影响超出了感染，因为包括癌症和自身免疫性疾病在内的疾病与宿主和微生物之间的异常相互作用有关。鉴于这些相互作用的重要性，上皮细胞具有独特的机制，使粘膜组织能够区分真菌和病原微生物。真菌白色念珠菌（C.alb）是一种微生物的例子，它可以在健康人群中作为真菌存在，但在不健康的人群中成为一种危险的病原体，导致严重和潜在的致命疾病。事实上，念珠菌感染经常被发现是第三或第四最常见的医院获得性血流感染，导致约40%的人死亡，因此是医疗保健提供的严重负担。鉴于绝大多数的血液白念珠菌感染是通过粘膜表面获得的，因此了解白念珠菌与健康上皮组织相互作用的机制以及确定正常反应被破坏时促进感染和疾病的真菌因素至关重要。目前，我们对促进粘膜感染的真菌因素知之甚少，我们最近的工作有助于理解上皮细胞识别致病白念珠菌的机制以及这如何导致免疫保护。我们先前表明，C.alb感染导致免疫激活剂（细胞因子和趋化因子）的分泌，这些免疫激活剂招募特异性免疫细胞，以防止C.alb感染。最近，我们发现，为了激活这种保护性免疫过程，上皮细胞识别丝状、“侵入性”形式的白念珠菌菌丝上的一种特异性蛋白质（CaEce 1 p）。CaEce 1 p是一种独特的菌丝蛋白，由8个相同大小的重复片段组成，这些片段分别由CaKex 2 p酶加工。我们提供了强有力的证据，证明CaEce 1 p（或其单个片段）是关键的真菌蛋白质，它告知健康宿主存在已变得危险的微生物。该提案旨在证明CaEce 1 p对白念珠菌的功能，CaEce 1 p如何定位于菌丝表面，以及关键的CaEce 1 p片段激活上皮细胞。这将为基础真菌生物学和支持健康中白念珠菌与宿主相互作用的机制提供重要的新认识。该项目将确定CaEce 1 p不仅是开发新的抗真菌药物的新靶点，也是开发新的疫苗，佐剂，诊断测试和真菌感染生物标志物的新靶点。另外令人感兴趣的是CaEce 1 p和玉米黑粉菌的菌丝特异性Rep 1蛋白之间的结构相似性，玉米黑粉菌是一种致病植物真菌，可导致玉米黑穗病。因此，与CaEce 1 p获得的功能数据也可能为未来的研究调查植物真菌的发病机制提供有价值的基础。

项目成果

Processing of Candida albicans Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence.

白色念珠菌ECE1P的处理对于念珠菌素的成熟和真菌毒力至关重要。

• DOI: 10.1128/mbio.02178-17
• 发表时间: 2018-01-23
• 期刊: mBio
• 影响因子: 6.4
• 作者: Richardson JP;Mogavero S;Moyes DL;Blagojevic M;Krüger T;Verma AH;Coleman BM;De La Cruz Diaz J;Schulz D;Ponde NO;Carrano G;Kniemeyer O;Wilson D;Bader O;Enoiu SI;Ho J;Kichik N;Gaffen SL;Hube B;Naglik JR
• 通讯作者: Naglik JR

Cell cycle-independent phospho-regulation of Fkh2 during hyphal growth regulates Candida albicans pathogenesis.

• DOI: 10.1371/journal.ppat.1004630
• 发表时间: 2015-01
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Greig JA;Sudbery IM;Richardson JP;Naglik JR;Wang Y;Sudbery PE
• 通讯作者: Sudbery PE

Clotrimazole dampens vaginal inflammation and neutrophil infiltration in response to Candida albicans infection.

克霉唑可抑制白色念珠菌感染引起的阴道炎症和中性粒细胞浸润。

• DOI: 10.1128/aac.01244-13
• 发表时间: 2013
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Wilson D

Production of water-soluble few-layer graphene mesosheets by dry milling with hydrophobic drug.

• DOI: 10.1021/la5038475
• 发表时间: 2014-12
• 期刊: Langmuir : the ACS journal of surfaces and colloids
• 作者: N. Rubio;Rui Serra-Maia;H. Kafa;Kuo-Ching Mei;E. Pach;William Luckhurst;M. Zloh;F. Festy;J. Richardson;J. Naglik;B. Ballesteros;K. Al‐Jamal

Epithelial discrimination of commensal and pathogenic Candida albicans.

共生和致病性白色念珠菌的上皮细胞辨别。

• DOI: 10.1111/odi.12395
• 发表时间: 2016
• 期刊: Oral diseases
• 影响因子: 3.8
• 作者: Tang SX