Completed Infection & Immunity Cells, Biochemistry & Physiology

Fungal peptide toxins in pathogenicity and immunity

Funder Wellcome Charity-funded
Recipient organisation King's College London
Funding £2.1M
Period Apr 2019 — Mar 2024

In plain English

AI plain-English summary

Fungal infections kill around 1.5 million people each year, yet the molecular weapons fungi use to attack human cells have remained largely unknown—until the discovery of candidalysin, a toxin secreted by the yeast *Candida albicans* that punches holes in host cell membranes. This matters because doctors have few effective treatments for severe fungal infections, and resistance to existing antifungal drugs is growing. Without understanding how fungi cause disease and how the immune system fights back, developing new therapies is guesswork. Candidalysin is the first such toxin found in any human fungal pathogen, and the researchers have now identified many similar peptide toxins in other disease-causing fungi. The team will use structural biology, biochemistry, and immunology to determine exactly how candidalysin forms pores in cells, how epithelial cells detect and respond to the toxin, and which host proteins protect against it. They will also test whether the newly discovered toxins play similar roles in other fungal infections. This is fundamental science with no immediate clinical application. But understanding the precise molecular handshake between fungal toxins and human immune defences could eventually point toward vaccines or immunotherapies that train the body to neutralise these toxins—a strategy that has worked for bacterial infections but remains unexplored for fungi.

View original technical description
Fungal infections kill ~1.5 million individuals each year. Despite this, the pathogenic processes promoting fungal infections and the host immune responses preventing infections are largely unknown. Our discovery of the pore-forming peptide toxin “candidalysin”, secreted by Candida albicans, represents a seminal advance in understanding fungal pathogenesis, as human pathogenic fungi were not known to possess such toxins. Candidalysin is critical for C.albicans virulence and induction of innate immunity, and belongs to a small family of toxins produced by hypha-producing Candida spp. We have now discovered a multitude of new peptide toxins in other pathogenic fungi. This proposal will employ a multi-disciplinary approach, blending structural biology, biophysical, biochemical, molecular, genetic, cellular and immunological methodologies to: - Determine the molecular structure of candidalysin pores. - Delineate the epithelial cellular mechanisms activated by candidalysin. - Determine the epithelial-related proteins that drive protection against candidalysin. - Determine the importance of other peptide toxins in fungal disease and innate immunity. This work will determine the mechanisms by which candidalysin and peptide toxins promote fungal disease and innate immunity. It will develop a new field of science, improve understanding of innate immunity, and identify novel fungal and host targets for developing new immunotherapies and vaccines.

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Researchers

Julian Naglik (EPMC Awardee)

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Original classification

Investigator Award in Science

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