Molecular understanding of ferroptosis in Cryptococcus neoformans

• Grant number: 25/11349-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: December 01, 2025
• End date: November 30, 2026
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Kelly Ishida
• Grantee: Daniel Felipe Freitas de Jesus
• Supervisor: James Warren Kronstad
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of British Columbia, Vancouver (UBC), Canada
• Associated to the scholarship: 24/01658-4 - Ferroptosis in Cryptococcus neoformans: molecular, cellular and microbiological approaches, BP.PD

Abstract

Cryptococcus is the etiological agent of cryptococcosis, and it is estimated that 147,000 deaths and more than 190,000 cases of the disease occur annually worldwide. This high mortality is associated with the immunosuppression of patients, the virulence factors of the fungus, the limited arsenal of commercially available antifungals, and the emergence of strains resistant to therapeutic options. To address this issue, numerous approaches have been undertaken to discover new targets and new therapeutic molecules. In the past decade, the ferroptosis pathway (iron-dependent cell death) in mammalian cells has achieved medical interest due to its notable susceptibility to activation in chemotherapy-resistant and metastasis-prone tumor cells. It is known that these death mechanisms are conserved among organisms, especially between fungal and mammalian eukaryotic cells. Recently, we observed through comparative genomics and qPCR assays, the presence of ferroptosis pathway genes in Cryptococcus neoformans (XC-like transporter, YGSC-like, GPX4-like, ACLS4-like, LPCAT3-like). Additionally, C. neoformans yeasts were highly susceptible to death in the presence of FeSO4 (Fe2+), suggesting for the first time the occurrence of ferroptosis in this fungus. Thus, to better understand ferroptosis in Cryptococcus, we aim to study the role of key genes (GPX4-like and ACLS4-like) in this death pathway, as well as their role in fungal virulence, by generating mutant strains with these genes repressed. (AU)