Abstract
Mucormycosis is an emerging angio-invasive infection caused by Mucorales that presents unacceptable mortality rates. Iron uptake has been related to mucormycosis, since serum iron availability predisposes the host to suffer this infection. In addition, iron uptake has been described as a limiting factor that determines virulence in other fungal infections, becoming a promising field to study virulence in Mucorales. Here, we identified a gene family of three ferroxidases in Mucor circinelloides, fet3a, fet3b and fet3c, which are overexpressed during infection in a mouse model for mucormycosis, and their expression in vitro is regulated by the availability of iron in the culture media and the dimorphic state. Thus, only fet3a is specifically expressed during yeast growth under anaerobic conditions, whereas fet3b and fet3c are specifically expressed in mycelium during aerobic growth. A deep genetic analysis revealed partially redundant roles of the three genes, showing a predominant role of fet3c, which is required for virulence during in vivo infections, and shared functional roles with fet3b and fet3c during vegetative growth in media with low iron concentration. These results represent the first described functional specialization of an iron uptake system during fungal dimorphism.
Highlights
Mucormycosis is an emerging fungal infection caused by species of the order Mucorales that presents unacceptably high mortality rates
We searched the genome of the genetic fungal model M. circinelloides for genes encoding proteins with high similarity to FET3 of S. cerevisiae[25], which is a partner of the permease FTR1 in the high-affinity iron uptake system and a putative candidate to play an important role in mucormycosis
Home.html) was searched by BLAST to identify orthologous genes of the S. cerevisiae ferroxidase FET325 (ID: YMR058W-t26_1; FugiDB.org), resulting in the identification of three putative ferroxidase/multicopper oxidases in this fungus
Summary
Mucormycosis is an emerging fungal infection caused by species of the order Mucorales that presents unacceptably high mortality rates. The role of the FRE family of plasma membrane reductases in iron uptake was studied in Saccharomyces cerevisiae, in which several homologous metalloreductases were described with a redundant function that confers the ability to utilize iron from a variety of sources[27] These iron reductases have been associated to virulence in the human pathogen Cryptococcus neoformans, in which mutants lacking the gene FRE2 showed attenuated virulence. Mutants in ftr[1] are compromised in their ability to acquire iron during in vitro culturing and present reduced virulence during in vivo infections in mouse models[20,21] These studies indicate a crucial role of the high-affinity iron uptake system in the development of mucormycosis, correlating the susceptibility of patients presenting unbalanced levels of available iron to this infection. The generation of single and double mutants in this gene family implicated ferroxidases both in vegetative growth on media with low iron concentration and virulence in a mammalian model
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