Elucidating the role of Candida albicans Ece1 peptides

真菌每年感染数十亿人，但作为病原体仍在很大程度上被低估。白色念珠菌是人类最常见的致病真菌之一。这种真菌在大多数人的粘膜表面定居为无害的共生体，但在某些诱因条件下可引起浅表甚至威胁生命的系统性感染。白色念珠菌的一个关键毒力属性是它能够经历形态上的酵母到菌丝的转变。这种转变得到了很好的研究，并以一个非常不同的转录程序为特征。在菌丝形成过程中表达的核心基因是ECE1，它编码一种由八个多肽(PI-VIII)组成的多蛋白，这些多肽由细胞内的蛋白酶加工并分泌到细胞外空间。其中一种多肽PIII是念珠菌素的前体，念珠菌素是在人类致病真菌中发现的第一种真菌多肽毒素。念珠菌素能够插入宿主细胞膜形成溶细胞孔，在粘膜感染、炎性小体激活和上皮移位过程中发挥重要作用。然而，Ece1作为连接多肽的多蛋白结构的原因仍不清楚。本项目的目的是研究非念珠菌素Ece1肽(NCEPs，PI-II，IV-VIII)对白色念珠菌生物学的作用及其与宿主的相互作用。根据尚未发表的初步数据，我们认为NCEP有三个潜在的、部分重叠的关键功能：(1)它们是真菌过程所必需的；(2)它们调节念珠菌素的功能；(3)它们作为效应肽，调节寄主反应，类似于病原菌和真菌植物病原菌中的效应物。详细地，我们将(1)阐明NCEP在菌丝形成、真菌信号或通讯以及真菌对自身定向念珠菌素毒性的保护作用；(2)我们将研究NCEP在Ece1/Candidalysin功能中的作用，如Ece1折叠、加工或分泌以及将念珠菌素输送到宿主细胞膜；(3)我们将剖析效应肽假说，包括NCEP在真菌-宿主交流中的作用，它们作为细胞外或细胞内效应物的潜在作用，多肽向宿主的传递，多肽靶标，宿主活动的调节以及共生和感染的后果。这些研究将为白念珠菌共生和致病所需的基本过程提供新的见解。

Fungi infect billions of people every year, but remain largely under-appreciated as pathogens. One of the most common human pathogenic fungi is Candida albicans. This fungus colonizes mucosal surfaces of most humans as harmless commensal, but can cause superficial or even life threatening systemic infections under certain predisposing conditions.A key virulence attribute of Candida albicans is its ability to undergo a morphological yeast-to-hypha transition. This transition is well-studied and is characterized by a very distinct transcription program. Among the core genes expressed during hyphal formation is ECE1, which encodes a polyprotein consisting of eight peptides (PI-VIII) processed by intracellular proteases and secreted into the extracellular space. One of these peptides, PIII, is the precursor of Candidalysin, the first fungal peptide toxin discovered in a human pathogenic fungus. Candidalysin is able to intercalate into host membranes to produce cytolytic pores and was shown to play crucial roles during mucosal infections, inflammasome activation and epithelial translocation. However, the reason why Ece1 is structured as a polyprotein of concatenated peptides remains unknown. The aim of this project is to investigate the role of non-Candidalysin Ece1 peptides (NCEPs, PI-II, IV-VIII) for the biology of C. albicans and its interaction with the host. Based on preliminary unpublished data, it is proposed that NCEPs have three potential, partial overlapping, key functions: (1) they are required for fungal processes; (2) they modulate Candidalysin functions; (3) they act as effector peptides and modulate host responses analogous to effectors in pathogenic bacteria and fungal plant pathogens.In detail, we will (1) elucidate the role of NCEPs for hypha formation, fungal signalling or communication and fungal protection against self-directed Candidalysin toxicity; (2) we will investigate the role of NCEPs for Ece1/Candidalysin functions such as Ece1 folding, processing or secretion and delivery of Candidalysin to host cell membranes; (3) we will dissect the effector peptide hypothesis including the role of NCEPs for fungus-host communication, their potential role as extracellular or intracellular effectors, delivery of the peptides to the host, peptide targets, modulation of host activities and consequences for commensalism and infection.It is anticipated that these studies will provide novel insight into fundamental processes required for commensalism and pathogenicity of C. albicans.