Host response associated with dormant and persister cells of C. neoformans (VBNCrypto)

• Grant number: 25/05264-3
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2025
• End date: September 30, 2029
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Agreement: ANR
• Principal Investigator: Carlos Pelleschi Taborda
• Grantee: Carlos Pelleschi Taborda
• Principal researcher abroad: Alexandre Alanio
• Institution abroad: Institut Pasteur , France
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Gabriel Davi Marena ; Gil Benard ; Maria da Gloria Sousa Stafocker ; Ruchi Agrawal

Abstract

Species of Cryptococcus are a major cause of invasive fungal infections and are responsible for 20% of the total fungal infections caused by invasive fungi. Cryptococcal diseases affect 194,000 people worldwide, with 147,000 deaths (75·8%) annually. The main clinical presentation is cryptococcal meningitis, although lung cryptococcosis is also frequent but not as lethal. Dissemination of bone marrow and other organs is also seen in immunocompromised patients. Cryptococcus neoformans has recently been classified by the World Health Organization (WHO) as a critical pathogen indicating that this fungal pathogen requires the greatest attention from the healthcare system to academic and industrial research. The mortality rate is 100% in cryptococcal meningitis patients without the treatment, which was reduced to 55% at 10 weeks and >70% at one year with fluconazole monotherapy. The currently available best combination therapy with Amphotericin B (AMB) plus flucytosine, however, reduced the mortality rate by up to 20% in developed countries and up to 75% in less privileged countries. Clinical relapse/disease recurrence is another issue that adds to the high morbidity and mortality associated with Cryptococcosis. This project proposal is focused on phenotypic/population heterogeneity in C. neoformans. Heteroresistance, antifungal persistence, biofilm, dormancy, and viable but not culturable (VBNC) phenotypes are the results of population heterogeneity in C. neoformans and are universally displayed by all the studied strains of C. neoformans. Heteroresistance provides a temporary tolerance during azole(s) treatment, by chromosomal aneuploidy and heterochromatin formation. Biofilm protects the cryptococcal population from various stresses including antifungal treatment. Dormancy and VBNC phenotypes allow C. neoformans to survive in the host for years during latency. Lastly, antifungal persister cells (AFPC) help C. neoformans tolerate very high amounts of fungicidal drugs that are otherwise lethal. VBNCrypto aims to understand the advantages that VBNC and AFPC phenotypes provide to the yeast population during Cryptococcus-immune system interactions and disease progression in the host. (AU)