Elucidating the role of Candida albicans Ece1 peptides

• Applicant: Professor Dr. Bernhard Hube
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421469702

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 Based on preliminary unpublished data, it is proposed that NCEPs have three potential, partial overlapping, key functions: (1) they are required for fungal processes; (2) they modulate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

• DFG Programme: Research Grants