Role of Extracellular Vesicles produced by Candida haemulonii in pathogenesis and fungal multiresistance

• Grant number: 22/08432-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): December 01, 2022
• Effective date (End): March 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Fausto Bruno dos Reis Almeida
• Grantee: Bianca Teixeira Morais de Oliveira
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 21/06794-5 - Fungal extracellular vesicles: immunomodulation and cellular communication, AP.JP2

Abstract

Candida haemulonii is a multifaceted complex of Candida "non-albicans" species in evidence, classified as multi-resistant to available antibiotics in clinic. One of the species virulence strategies concerns in release extracellular vesicles (EVs) that could support the infection through bidirectional communication with host. Results about this EVs obtained by Nanoparticle Tracking Analysis and Multiomics, were verified in the master's degree, process number: 2020/02841-6, already submitted to selective editorial policy journal. This EVs demonstrated a prevalence of exosomes population with concentration of 1010 particles/ml, and size ranging 25 to 400 nm. Moreover, we characterize the morphology and dimensions of these EVs by Transmission Electronical Microscopy, besides we evidence the complex composition of these vesicles due the presence of microRNAs and functional proteins for its prevalence and pathogenicity. Furthermore, preliminary assays suggest that RAW 264.7 macrophages exposition for fungal EVs, in different conditions, induced cellular immunomodulation. However, there is gaps about the understanding of EVs in this yeast virulence and resistance, making difficult directed therapy in serious cases. In this perspective, this project aims to evaluate the C. haemulonii EVs roles in the species pathogenicity through In Vitro and In Vivo assays, employing incubation with VEs inhibitors (imipramine and GW4869), which changes the lipidic metabolism at exosome's formation and its possible association with classicals antifungals (fluconazole and amphotericin B), antibiotics that all clade present resistance. With this, we intend to directly investigate the relationship between EVs functions and fungal virulence, based on the hypothesis that C. haemulonii EVs performs critical role in resistance and virulence. Besides, these drugs use and its synergism, could support the host defense and promote news therapy development or redirected these drugs, each one with targets pharmacological already established.