Incorporation of host cholesterol as a mechanism of resistance to azoles in eukaryotic pathogens

• Grant number: 25/04418-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: May 01, 2025
• End date: April 30, 2027
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Sergio Schenkman
• Grantee: Gabriella Luisa Pasini Moraes
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 21/10599-3 - The Antimicrobial Resistance Institute of São Paulo (The Aries Project), AP.CEPID

Abstract

Cholesterol is the main component of the plasma membrane in most eukaryotes. Some fungi and parasites, despite not synthesizing cholesterol as a membrane ester, but rather ergosterol, uptake cholesterol from the environment and use it for their metabolism. In Candida albicans and Nakaseomyces glabratus, mechanisms for the uptake of cholesterol from the host serum have already been described, for the replenishment of steroids in the presence of azoles, which inhibit ergosterol synthesis, suggesting that this is a resistance mechanism; however, this mechanism has not been described in Candida tropicalis. Trypanosoma cruzi, on the other hand, incorporates cholesterol through the endocytosis of LDL molecules and stores this cholesterol in the reservosome or in lipid bodies located in the cytoplasm; however, it has not been described whether this cholesterol can act as a resistance mechanism in this parasite to azole compounds. Therefore, for this project, we propose to elucidate how the incorporation of cholesterol affects resistance and survival in ergosterol synthesis pathway inhibitors in these two models. a) In Candida tropicalis, we intend to verify whether susceptibility to azoles is related to the presence of cholesterol in both resistant and sensitive isolates. b) In Trypanosoma cruzi, we intend to similarly verify how the endocytosis of macromolecules containing cholesterol is related to the synthesis of ergosterol. In both cases, we will seek to elucidate whether the ergosterol synthesis pathway is regulated by the presence of cholesterol.