Elucidating the role of Candida albicans Ece1 peptides

真菌每年感染数十亿人，但作为病原体，它们在很大程度上仍被低估。最常见的人类致病真菌之一是白色念珠菌。白色念珠菌是一种寄生于人体粘膜表面的真菌，对人体无害，但在某些条件下可引起浅表甚至危及生命的全身性感染。这种转变是很好的研究，其特点是一个非常独特的转录程序。在菌丝形成过程中表达的核心基因是ECE 1，其编码由8个肽（PI-VIII）组成的多蛋白，所述肽由细胞内蛋白酶加工并分泌到细胞外空间中。这些肽之一，PIII，是在人类致病真菌中发现的第一种真菌肽毒素--沙冬青素能够插入宿主细胞膜以产生溶细胞孔，并且显示在粘膜感染、炎性小体活化和上皮移位过程中起关键作用。然而，为什么Ece 1的结构作为一个多蛋白的串联肽仍然未知。本项目的目的是研究非胰蛋白酶Ece 1肽（NCEP，PI-II，IV-VIII）在C.白色念珠菌及其与宿主的相互作用。基于未发表的初步数据，提出NCEP具有三种潜在的、部分重叠的关键功能：（1）它们是真菌过程所必需的;（2）它们调节放线菌素的功能;（3）它们作为效应肽，类似于病原细菌和真菌植物病原体中的效应子调节宿主反应。（2）我们将研究NCEP对Ece 1/Escherichia dalysin功能的作用，例如Ece 1折叠、加工或分泌以及将Escherichia dalysin递送到宿主细胞膜;（3）我们将剖析效应肽假说，包括NCEP在真菌-宿主通讯中的作用，这些研究将为深入了解C.白色念珠菌

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 Based on preliminary unpublished data, it is proposed that NCEPs have three potential, partial overlapping, key functions: (1) they are required for fungal processes; (2) they modulate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.