The Role of Extracellular Vesicles and Sit4 Phosphatase in Pathogenicity

• Grant number: 25/05600-3
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: September 01, 2025
• End date: November 30, 2025
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Fausto Bruno dos Reis Almeida
• Grantee: Júlia Leão Froldi
• Supervisor: Yong-Sun Bahn
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Yonsei University, South Korea
• Associated to the scholarship: 24/01074-2 - Immunoregulatory role of extracellular vesicles from Candida albicans and Aspergillus fumigatus, BP.MS

Abstract

Fungal infections represent an escalating global health threat, affecting over 150 million individuals annually and resulting in approximately 4 million deaths per year. Invasive fungal infections, primarily caused by Candida spp., Aspergillus spp., and Cryptococcus spp., involve multiple virulence factors. Among these, biofilm formation plays a pivotal role by creating structured microbial communities encased in an extracellular matrix (ECM) that enhances fungal adhesion, provides protection against environmental threats, and facilitates immune evasion. The ECM, predominantly composed of polysaccharides, is crucial for biofilm integrity and antifungal resistance. Extracellular vesicles (EVs) are lipid bilayer structures secreted by fungi that transport proteins, lipids, nucleic acids, and enzymes. EVs play a pivotal role in fungal communication, biofilm formation, and virulence by delivering essential ECM components, modulating immune responses, and transferring virulence factors. Despite their importance, the molecular mechanisms governing EV function remain poorly understood. A crucial but underexplored regulator of fungal adaptation and virulence is Sit4, a serine/threonine phosphatase from the type 2A phosphatase (PP2A) family. Sit4 is involved in cell division, stress response, and homeostasis, with evidence suggesting its strong influence on fungal pathogenicity. In Candida albicans and Aspergillus fumigatus, Sit4 mutations lead to reduced growth, impaired biofilm formation, and diminished virulence. However, its impact on EV-mediated processes remains unclear. This project aims to elucidate the role of Sit4 in fungal pathogenicity by investigating how Sit4 mutations affect EV composition and function. The main questions include whether EVs from Sit4 mutants carry altered cargo and how these changes influence fungal adhesion, immune evasion, and ECM production. By addressing the interplay between EVs and Sit4 phosphatase, this research seeks to fill a critical gap in our understanding of fungal adaptation and virulence. Understanding the role of Sit4 in EV-mediated processes is crucial for developing novel therapeutic strategies against fungal infections. By elucidating the mechanisms by which Sit4 influences fungal pathogenicity, this research will contribute significantly to the development of targeted interventions aimed at disrupting biofilm formation and enhancing antifungal efficacy. (AU)