Abstract
BackgroundFungal infections impact over 25% of the global population. For the opportunistic fungal pathogen, Cryptococcus neoformans, infection leads to cryptococcosis. In the presence of the host, disease is enabled by elaboration of sophisticated virulence determinants, including polysaccharide capsule, melanin, thermotolerance, and extracellular enzymes. Conversely, the host protects itself from fungal invasion by regulating and sequestering transition metals (e.g., iron, zinc, copper) important for microbial growth and survival.ResultsHere, we explore the intricate relationship between zinc availability and fungal virulence via mass spectrometry-based quantitative proteomics. We observe a core proteome along with a distinct zinc-regulated protein-level signature demonstrating a shift away from transport and ion binding under zinc-replete conditions towards transcription and metal acquisition under zinc-limited conditions. In addition, we revealed a novel connection among zinc availability, thermotolerance, as well as capsule and melanin production through the detection of a Wos2 ortholog in the secretome under replete conditions.ConclusionsOverall, we provide new biological insight into cellular remodeling at the protein level of C. neoformans under regulated zinc conditions and uncover a novel connection between zinc homeostasis and fungal virulence determinants.
Highlights
Fungal infections impact over 25% of the global population
We recently explored the impact of zinc availability in the bacterial pathogen, Klebsiella pneumoniae through proteomic profiling and uncovered a novel connection between zinc homeostasis and capsule regulation [22]
Modulating zinc availability promotes cellular remodeling of the C. neoformans proteome To explore the relationship between zinc availability and protein production in C. neoformans, we profiled the cellular proteome and secretome under zinc-limited and -replete
Summary
Fungal infections impact over 25% of the global population. For the opportunistic fungal pathogen, Cryptococcus neoformans, infection leads to cryptococcosis. C. neoformans is an opportunistic fungus found ubiquitously within the environment and is equipped with sophisticated virulence determinants, including a polysaccharide capsule, melanin, thermotolerance, and extracellular enzymes [7]. This arsenal of determinants provides resources to modulate the host immune system and promote fungal survival in over 230,000 immunocompromised individuals (e.g., HIV/AIDS patients) annually [8, 9]. It is necessary to tightly regulate intracellular labile zinc content to maintain precise metal homeostasis Mammalian hosts manipulate these delicate margins of nutritional requirements as a sophisticated technique to combat pathogenic microbes from securing essential micronutrients. These collective protective measures have been termed ‘nutritional immunity’ [24,25,26]
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