Active Infection & Immunity Genetics & Molecular Biology

Mechanistic insights into fungal pathogenicity and drug resistance using a novel lineage of Cryptococcus

Funder Wellcome Charity-funded
Recipient organisation University of Exeter
Funding £2.2M
Period Sept 2022 — Apr 2031

In plain English

AI plain-English summary

A newly discovered strain of *Cryptococcus* from Zambia is both highly drug-resistant and surprisingly bad at causing disease, offering a natural experiment to unpick how this fungus kills over 130,000 people each year. The problem is stark: *Cryptococcus* causes more than 220,000 cases of meningitis and other infections annually, with mortality driven by the fungus’s ability to change shape, evade the immune system, and evolve resistance to the few available antifungal drugs. Current treatments are failing, and the genetic and epigenetic mechanisms behind these traits remain poorly understood. This project will compare gene activity across all known *Cryptococcus* lineages when they infect immune cells and when exposed to drugs, then build a gene deletion library from the new strain to test which genes control virulence and resistance in animal models. The researchers will also map how chromatin structure—the physical packaging of DNA—changes as the fungus shifts between its pathogenic and non-pathogenic forms. If successful, this work will identify specific molecular targets for new antifungal drugs and reveal how drug resistance emerges at the epigenetic level. The findings could ultimately inform better treatments for cryptococcal meningitis, a disease that kills roughly one in five of those infected.

View original technical description
Cryptococcus causes one of the most impactful fungal diseases in humans and is responsible for >220,000 cases and >130,000 deaths per year. Mortality is amplified by both innate and evolved drug resistance by this fungus and its ability for morphogenesis. I recently discovered a new genetically-distinct lineage of Cryptococcus through whole-genome sequencing of environmental isolates from Zambia, which has a reduced ability to cause disease in the murine model of infection and very high levels of antifungal resistance. In this project I will exploit this new lineage to gain mechanistic insight into fungal pathogenicity and drug resistance. I will perform comparative transcript profiling of all Cryptococcus lineages following infection of macrophages and antifungal drug exposure to identify genes responsible for those crucial phenotypic differences. Using the new lineage, I will construct a gene deletion library of unique gene differences and experimentally test them in relevant animal models to characterise novel drivers of pathogenicity. The genetic basis for pathogenicity and drug resistance will be complimented by delineating epigenetic determinants of those traits by constructing a comprehensive chromatin atlas across pathogenic morphotypes. This project will deliver new knowledge to address the important human health issues of cryptococcal infection and microbial drug resistance.

View the original record at the funder ↗

Researchers

Rhys Farrer (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

An evolutionary population genomics approach to determine the genetic basis of virulence in the pathogenic fungus Cryptococcus neoformans
3D genomics and epigenomics underpinning cryptococcal drug resistance
Macrophage inflammatory activation and behaviour in immunity to infection
Regulation of genome and epigenome plasticity in adaptation and virulence of the human fungal pathogen Cryptococcus neoformans.
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Original classification

Career Development Award

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