Antifungal activity of dendritic cell lysosomal proteins against Cryptococcus neoformans

Benjamin N Nelson,Sierra Posey,Emma Maritz,Karen L Wozniak,Janakiram Seshu,Brittney Conn,Savannah G Beakley

doi:10.1038/s41598-021-92991-6

Benjamin N Nelson, Sierra Posey + Show 5 more

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https://doi.org/10.1038/s41598-021-92991-6

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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.

Highlights

Cryptococcal meningitis is a life-threatening disease among immune compromised individuals that is caused by the opportunistic fungal pathogen Cryptococcus neoformans
The prevalence between AIDS and cryptococcosis is so high that the CDC has named it an AIDS-defining illness, and the occurrence of cryptococcal meningitis is most prevalent in sub-Saharan A frica[7,8]
An analysis of the 2014 Joint UN Programme on HIV and AIDS showed that of the 223,100 yearly cases of cryptococcal meningitis, 73% occurred in sub-Saharan Africa (162,500 cases) with estimated yearly death totals of 181,100 and 135,900 worldwide and in sub-Saharan Africa, respectively[9]

Summary

Introduction

Cryptococcal meningitis is a life-threatening disease among immune compromised individuals that is caused by the opportunistic fungal pathogen Cryptococcus neoformans. 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. The purified contents of DC lysosomes can kill the fungus in vitro in a dose-dependent manner[26,36] These studies illustrate that it is the components of the lysosome that act upon the pathogen. It has been shown that one component within the DC lysosome can inhibit the growth of this yeast: cathepsin B This cysteine protease is able to form a hole in the cell wall that results in osmotic lysis of C. neoformans[26]. Further studies are underway in our laboratory to determine cathepsin B’s mechanism of action against C. neoformans

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