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Candidalysins: Mechanistic function of a novel family of fungal peptide toxins

念珠菌溶素：新型真菌肽毒素家族的机制功能

基本信息

批准号：
BB/N014677/1
负责人：
Julian Naglik
金额：
$ 62.02万
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：
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=BB%2FN014677%2F1
关键词：
Candidalysins Mechanistic function novel family

项目摘要

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. Cytolytic proteins and peptide toxins are critical virulence factors of bacterial pathogens and play a major role in bacterial disease. Until very recently, human pathogenic fungi were not known to possess such toxins. The human fungal pathogen Candida albicans, the causative agent of thrush, causes millions of infections annually in people worldwide. An explanation for precisely how this fungus is able to cause mucosal disease has remained at the forefront of medical mycology and immunology for several decades. We have recently identified a secreted peptide toxin (Candidalysin) as an essential factor required for C. albicans infection at mucosal surfaces. This is the first cytolytic peptide toxin to be discovered in any human pathogenic fungus. Our work has shown that Candidalysin interacts with the membrane of epithelial cells, causing membrane damage, inflammation and destruction of host tissues. Production of this toxin by C. albicans is now understood to be a critically important step that facilitates mucosal infection and disease progression. Importantly, we have now identified similar Candidalysin toxins in the related fungal species C. dubliniensis and C. tropicalis, which are also pathogenic. Together with C. albicans, these fungi represent an immense health burden on the global population. The discovery of three Candidalysins identifies these toxins as a conserved family used by pathogenic Candida species to cause disease. Currently, there are no vaccines for Candida infections and the incidence of fungal pathogens acquiring resistance to commonly prescribed antifungal drugs is rising. Given their essential role in mucosal infection, understanding how this family of fungal toxins damage mucosal surfaces is critically important, and will pave the way towards therapeutic intervention that enables us to control and prevent disease progression. This proposal aims to identify exactly how Candidalysins interact with epithelial cell membranes to cause damage and infection. The findings of this work will be pivotal to our future understanding of fungal pathogenesis and will enable us to develop new strategies to engage with fungal infections to control their impact on the human population. This project will identify the Candidalysin family as 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.

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。细胞溶解蛋白和肽毒素是细菌病原体的重要毒力因子，在细菌疾病中起着重要作用。直到最近，人们才知道人类致病真菌含有这种毒素。人类真菌病原体白色念珠菌是鹅口疮的病原体，每年在全世界造成数百万人感染。几十年来，这种真菌是如何引起粘膜疾病的解释一直处于医学真菌学和免疫学的前沿。我们最近发现一种分泌的肽毒素（念珠菌素）是粘膜表面白色念珠菌感染的必要因素。这是首次在人类致病真菌中发现的细胞溶解肽毒素。我们的工作表明，念珠菌素与上皮细胞的膜相互作用，导致膜损伤，炎症和宿主组织的破坏。白念珠菌产生这种毒素现在被认为是促进粘膜感染和疾病进展的一个至关重要的步骤。重要的是，我们现在已经在相关真菌物种C. dubliniensis和C. tropicalis中发现了类似的念珠菌素毒素，它们也具有致病性。与白色念珠菌一起，这些真菌对全球人口构成了巨大的健康负担。三种念珠菌素的发现将这些毒素确定为病原念珠菌物种用来引起疾病的保守家族。目前，还没有针对念珠菌感染的疫苗，真菌病原体对常用抗真菌药物产生耐药性的发生率正在上升。鉴于它们在粘膜感染中的重要作用，了解这一真菌毒素家族如何损害粘膜表面是至关重要的，并将为治疗干预铺平道路，使我们能够控制和预防疾病进展。本研究旨在明确念珠菌素是如何与上皮细胞膜相互作用导致损伤和感染的。这项工作的发现将对我们未来对真菌发病机制的理解至关重要，并将使我们能够制定新的策略来处理真菌感染，以控制它们对人类的影响。该项目将确定念珠菌素家族作为新的靶点，不仅用于开发新的抗真菌药物，而且用于开发新的疫苗、佐剂、诊断测试和真菌感染的生物标志物。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role for IL-1 Family Cytokines in Fungal Infections.

DOI：
10.3389/fmicb.2021.633047
发表时间：
2021
期刊：
Frontiers in microbiology
影响因子：
5.2
作者：
Griffiths JS;Camilli G;Kotowicz NK;Ho J;Richardson JP;Naglik JR
通讯作者：
Naglik JR

Candida albicans and candidalysin in inflammatory disorders and cancer.

DOI：
10.1111/imm.13255
发表时间：
2021-01
期刊：
Immunology
影响因子：
6.4
作者：
Ho J;Camilli G;Griffiths JS;Richardson JP;Kichik N;Naglik JR
通讯作者：
Naglik JR

IL-17 Receptor Signaling in Oral Epithelial Cells Is Critical for Protection against Oropharyngeal Candidiasis.

DOI：
10.1016/j.chom.2016.10.001
发表时间：
2016-11-09
期刊：
Cell host & microbe
影响因子：
30.3
作者：
Conti HR;Bruno VM;Childs EE;Daugherty S;Hunter JP;Mengesha BG;Saevig DL;Hendricks MR;Coleman BM;Brane L;Solis N;Cruz JA;Verma AH;Garg AV;Hise AG;Richardson JP;Naglik JR;Filler SG;Kolls JK;Sinha S;Gaffen SL
通讯作者：
Gaffen SL

Fungal Toxins and Host Immune Responses.