Abstract
In fungi, metals are associated with the expression of virulence factors. However, it is unclear whether the uptake of metals affects their pathogenicity. This study aimed to evaluate the effect of iron/copper in modulating pathogenicity and proteomic response in two clinical isolates of C. neoformans with high and low pathogenicity. Methods: In both isolates, the effect of 50 µM iron and 500 µM copper on pathogenicity, capsule induction, and melanin production was evaluated. We then performed a quantitative proteomic analysis of cytoplasmic extracts exposed to that combination. Finally, the effect on pathogenicity by iron and copper was evaluated in eight additional isolates. Results: In both isolates, the combination of iron and copper increased pathogenicity, capsule size, and melanin production. Regarding proteomic data, proteins with increased levels after iron and copper exposure were related to biological processes such as cell stress, vesicular traffic (Ap1, Vps35), cell wall structure (Och1, Ccr4, Gsk3), melanin biosynthesis (Hem15, Mln2), DNA repair (Chk1), protein transport (Mms2), SUMOylation (Uba2), and mitochondrial transport (Atm1). Increased pathogenicity by exposure to metal combination was also confirmed in 90% of the eight isolates. Conclusions: The combination of these metals enhances pathogenicity and increases the abundance of proteins related to the main virulence factors.
Highlights
In eukaryotic cells, transition metals (manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), and copper (Cu)) are involved in redox reactions and are necessary for many important biological processes
We evaluated the effect of iron and copper on pathogenicity, capsular size, and melanin production in clinical isolates of C. neoformans
Since the pre-incubation with 50 μM iron and/or 500 μM copper resulted in a significant change in the pathogenicity of clinical isolates, we investigated the effect of these metals on different virulence factors
Summary
Transition metals (manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), and copper (Cu)) are involved in redox reactions and are necessary for many important biological processes. They play a role in infection processes in different fungi and serve as cofactors for several enzymes related to the expression of virulence factors, such as superoxide dismutase (SOD), metalloproteases, and preceding laccases [1,2]. Metals are related to the activation and regulation of the immune system [3,4]. Cryptococcus neoformans, iron and copper regulate the expression of virulence factors and various intracellular signaling pathways, especially those involved in adaptation to environmental changes and stress conditions [5,6]
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