The Homeostasis of Iron, Copper, and Zinc in Paracoccidioides Brasiliensis, Cryptococcus Neoformans Var. Grubii, and Cryptococcus Gattii: A Comparative Analysis

Abstract

Iron, copper, and zinc are essential for all living organisms. Moreover, the homeostasis of these metals is vital to microorganisms during pathogenic interactions with a host. Most pathogens have developed specific mechanisms for the uptake of micronutrients from their hosts in order to counteract the low availability of essential ions in infected tissues. We report here an analysis of genes potentially involved in iron, copper, and zinc uptake and homeostasis in the fungal pathogens Paracoccidioides brasiliensis, Cryptococcus neoformans var. grubii, and Cryptococcus gattii. Although prior studies have identified certain aspects of metal regulation in Cryptococcus species, little is known regarding the regulation of these elements in P. brasiliensis. We also present amino acid sequences analyses of deduced proteins in order to examine possible conserved domains. The genomic data reveals, for the first time, genes associated to iron, copper, and zinc assimilation and homeostasis in P. brasiliensis. Furthermore, analyses of the three fungal species identified homologs to genes associated with high-affinity uptake systems, vacuolar and mitochondrial iron storage, copper uptake and reduction, and zinc assimilation. However, homologs to genes involved in siderophore production were only found in P. brasiliensis. Interestingly, in silico analysis of the genomes of P. brasiliensis Pb01, Pb03, and Pb18 revealed significant differences in the presence and/or number of genes involved in metal homeostasis, such as in genes related to iron reduction and oxidation. The broad analyses of the genomes of P. brasiliensis, C. neoformans var. grubii, and C. gattii for genes involved in metal homeostasis provide important groundwork for numerous interesting future areas of investigation that are required in order to validate and explore the function of the identified genes and gene pathways.

Systemic Approach to Virulence Gene Network Analysis for Gaining New Insight into Cryptococcal Virulence

“…The largest group is ion sensors and transporters, which play a key role in regulating ion homeostasis and expression of virulence genes within the host (Silva et al, 2011; Jung et al, 2012). Proteins related to mannose and xylose transport and crosslinking are also numerous and these are the proteins required for construction of the immune-modulating capsule of C. neoformans .…”

Fungi between extremotolerance and opportunistic pathogenicity on humans

“…Similarly to all above discussed genes, genes for nonribosomal peptide synthetases (NRPSs) were not enriched in animal opportunists, although they are involved in the synthesis of important virulence determinants, such as ironchelating siderophores (Bushley and Turgeon 2010;Silva et al 2011), and toxins, such as enniatin, victorin, HC-toxin and AM-toxin (Walton 1996;Haese et al 1993). Iron overload in a host is known to exacerbate many infectious diseases, such as cryptococcosis in people infected with HIV, and conversely, iron withholding is an important defence strategy for mammalian hosts (Jung et al 2006).…”

Identification of human plasma proteins associated with the cell wall of the pathogenic fungusParacoccidioides brasiliensis

“…Iron availability is important for fungal growth (Arango & Restrepo, 1988), and the presence of siderophores has been demonstrated (Castaneda et al, 1988). In silico analysis showed that P. brasiliensis also has a highaffinity copper transport protein (Ctr3p) ortholog (Silva et al, 2011). The importance of copper homeostasis in Cryptococcus neoformans virulence was demonstrated, because it was linked to capsule production and inhibition of phagocytosis (Chun & Madhani, 2010).…”