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Published on: February 14, 2018
Antifungal activity of dendritic cell lysosomal proteins against Cryptococcus neoformans
Benjamin N Nelson1, Savannah G Beakley1, Sierra Posey1
1Department of Microbiology and Molecular Genetics, Oklahoma State University, 307 Life Science East, Stillwater, OK, 74078, USA.
Abstract:
Cryptococcal meningitis is a life-threatening disease among immune compromised individuals that is caused by the opportunistic fungal pathogen Cryptococcus neoformans. Previous studies have shown that the fungus is phagocytosed by dendritic cells (DCs) and trafficked to the lysosome where it is killed by both oxidative and non-oxidative mechanisms. While certain molecules from the lysosome are known to kill or inhibit the growth of C. neoformans, the lysosome is an organelle containing many different proteins and enzymes that are designed to degrade phagocytosed material. We hypothesized that multiple lysosomal components, including cysteine proteases and antimicrobial peptides, could inhibit the growth of C. neoformans. Our study identified the contents of the DC lysosome and examined the anti-cryptococcal properties of different proteins found within the lysosome. Results showed several DC lysosomal proteins affected the growth of C. neoformans in vitro. The proteins that killed or inhibited the fungus did so in a dose-dependent manner. Furthermore, the concentration of protein needed for cryptococcal inhibition was found to be non-cytotoxic to mammalian cells. These data show that many DC lysosomal proteins have antifungal activity and have potential as immune-based therapeutics.
Insights
Dendritic cell (DC) lysosomal proteins show potent antifungal activity against Cryptococcus neoformans, inhibiting fungal growth without harming host cells. These findings highlight potential immune-based therapies for cryptococcal meningitis.
Area of Science:
- Immunology
- Mycology
- Cell Biology
Background:
- Cryptococcal meningitis is a severe infection in immunocompromised individuals, caused by Cryptococcus neoformans.
- Dendritic cells (DCs) phagocytose C. neoformans, trafficking it to lysosomes for degradation via oxidative and non-oxidative mechanisms.
- Lysosomes contain numerous proteins and enzymes capable of degrading phagocytosed material, suggesting potential antimicrobial roles.
Purpose of the Study:
- To identify lysosomal proteins within dendritic cells (DCs).
- To investigate the anti-cryptococcal properties of these identified lysosomal proteins.
- To determine if lysosomal proteins can inhibit the growth of Cryptococcus neoformans.
Main Methods:
- Isolation and analysis of dendritic cell (DC) lysosomal contents.
- In vitro testing of purified lysosomal proteins against Cryptococcus neoformans.
- Dose-response assays to determine effective concentrations of antifungal proteins.
- Cytotoxicity assays to assess the safety of proteins on mammalian cells.
Main Results:
- Several DC lysosomal proteins demonstrated significant inhibition of C. neoformans growth in vitro.
- The antifungal effect of these proteins was dose-dependent.
- Effective concentrations of lysosomal proteins were non-cytotoxic to mammalian cells, indicating a favorable therapeutic window.
Conclusions:
- DC lysosomal proteins possess inherent antifungal activity against Cryptococcus neoformans.
- These findings suggest that lysosomal proteins could serve as a basis for novel immune-based therapeutic strategies against fungal infections.
- Further research into these proteins may lead to new treatments for cryptococcal meningitis and other invasive fungal diseases.
