Identification of a critical receptor mediating fungal recognition, epithelial activation and induction of mucosal innate immunity

粘膜（口腔、阴道、胃肠道）上皮是大多数微生物接触的初始组织，在保护人类免受多种感染方面具有极其重要的作用。在无害的“共生”微生物的情况下，这种微生物与上皮的接触要么导致无反应，要么导致致病的“致病”微生物的免疫激活。当这些正常反应被破坏时，就会出现大量的并发症，其影响超出了感染，因为包括癌症和自身免疫性疾病在内的疾病都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共生微生物和致病微生物。真菌白色念珠菌是一种微生物的例子，它可以在健康人群中作为共生菌存在，但在不健康的人群中成为一种危险的病原体，导致严重和可能致命的疾病。事实上，念珠菌感染现在是第三大最常见的医院获得性血液感染，是医疗保健提供的严重负担。鉴于绝大多数白色念珠菌感染是通过粘膜表面获得的，了解上皮组织通常如何将这种医学上重要的病原体限制在这些表面的共生状态是至关重要的。确定这些机制不仅对白色念珠菌感染，而且对控制粘膜表面的其他微生物具有相当大的价值。目前，我们对促进粘膜感染的真菌成分或识别白色念珠菌并协调免疫的宿主上皮蛋白（受体）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色念珠菌的机制以及这如何导致免疫保护。我们之前的研究表明，白色念珠菌感染导致免疫激活因子（细胞因子和趋化因子）的分泌，这些激活因子将特定的免疫细胞（中性粒细胞）招募到感染部位，然后与上皮细胞一起作用以防止白色念珠菌感染。最近，我们发现，为了激活这种保护性免疫过程，上皮细胞靶向一种特定的蛋白（Ece1p），这种蛋白位于白色念珠菌的“侵袭”形式，即菌丝上。目前尚不清楚的最重要的特征是识别白色念珠菌Ece1p并首先触发上皮活化的上皮受体。鉴定这种受体是了解上皮细胞如何对这种致病真菌作出反应和协调保护性粘膜免疫的关键。如果我们确定了受体，就可以开发针对该受体的药物，不仅用于治疗真菌感染，还用于治疗其他粘膜疾病。本研究的目的是确定Ece1p在白色念珠菌感染中的作用，鉴定识别白色念珠菌Ece1p的上皮受体，并确定白色念珠菌Ece1p-上皮受体相互作用在激活针对白色念珠菌粘膜感染的免疫保护中的重要性。本项目探讨了感染中一些最基本和最具挑战性的问题，即粘膜表面如何区分共生微生物和致病微生物，以及上皮组织如何启动保护性免疫反应。这项工作具有很强的医学意义，因为它不仅对开发新的免疫治疗真菌感染和更有效的抗真菌治疗具有重要意义，而且还有助于确定对抗其他粘膜疾病的新方法，并为患者利益操纵宿主免疫。

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. This microbial-epithelial encounter results in either no response 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 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 now the third most common hospital-acquired bloodstream infection and are a serious burden to healthcare provision. Given that the vast majority of C. albicans infections are acquired through mucosal surfaces, it is of paramount importance to understand how epithelial tissues normally restrict this medically-important pathogen to the commensal state at these surfaces. Identifying these mechanisms is of considerable value not just for C. albicans infections but also for controlling other microbes at mucosal surfaces. Presently, we have little knowledge of the fungal components promoting mucosal infections or the host epithelial proteins (receptors) recognising C. albicans and orchestrating immunity.Our recent work has been instrumental in understanding the mechanisms by which epithelial cells identify disease-causing C. albicans and how this results in immune protection. We previously showed that C. albicans infection leads to the secretion of immune activators (cytokines and chemokines) that recruit a specific immune cell (neutrophil) to the site of infection, which then act together with epithelial cells to protect against C. albicans infection. Recently, we found that to activate this protective immune process epithelial cells target a specific protein (Ece1p) on the 'invasive' form of C. albicans known as hyphae. The fundamentally important feature that is currently unknown is the epithelial receptor that recognises C. albicans Ece1p and triggers epithelial activation in the first instance. Identifying this receptor is key to understanding how epithelial cells respond to this pathogenic fungus and orchestrate protective mucosal immunity. If we identify the receptor, drugs can be developed to target this receptor for use in treating not only fungal infections but other mucosal diseases also. The aims of this proposal are to determine the role of Ece1p in C. albicans infection, to identify the epithelial receptor that recognises C. albicans Ece1p, and to determine the importance of the C. albicans Ece1p-epithelial receptor interaction in activating immune protection against C. albicans mucosal infection.This project explores some of the most fundamental and challenging issues in infection, namely how mucosal surfaces discriminate between commensal and pathogenic microbes and how epithelial tissues initiate protective immune responses. This work has strong medical importance as it will not only have implications for developing new immune-based treatments against fungal infections and more effective antifungal therapies, but also for defining new approaches to combat other mucosal diseases and to manipulate host immunity for patient benefit.