Role of miltefosine in the interaction of Cryptococcus neoformans with macrophages and in combination therapy with antifungals in a murine model of cryptococcosis

• Grant number: 24/01974-3
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Agreement: CNPq
• Principal Investigator: Kelly Ishida
• Grantee: Kelly Ishida
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 23/12190-0 - Molecules with antifungal potential on Candida and Cryptococcus and investigation of mechanisms of action: inhibition and cell death, AP.R
• Associated scholarship(s): 24/10991-9 - Role of miltefosine in the interaction of Cryptococcus neoformans with macrophages and in combination therapy with antifungals in a murine model of cryptococcosis., BP.JD

Abstract

Cryptococcosis is an opportunistic disease that causes meningitis. Cryptococcus spp. are considered ideal and facultative intracellular parasites, surviving in macrophages, and using them as a "Trojan horse" to penetrate the blood-brain barrier. This yeast-macrophage interaction is extremely important in the development of the disease and studies have shown that C. neoformans has developed a variety of mechanisms to prevent death by phagocytosis, being able to parasitize macrophages efficiently, surviving and proliferating within the phagosome. The treatment of cryptococcosis is limited and the available antifungals have some disadvantages such as drug interactions and high toxicity. Miltefosine has great potential for treating fungal infections, including cryptococcosis, and has an immunomodulatory effect. Therefore, the objective of this work is to investigate the fungicidal potential of miltefosine in the interaction of Cryptococcus neoformans yeasts with macrophages, as well as the antifungal efficacy of miltefosine, free or loaded-alginate nanoparticles, combined with conventional antifungals in the treatment of cryptococcosis in a murine model. (AU)