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Cu is an essential trace element for cell growth and proliferation. However, excess of Cu accumulation leads to cellular toxicity. Thus, precise and tight regulation of Cu homeostasis processes, including transport, delivery, storage, detoxification, and efflux machineries, is required. Moreover, the maintenance of Cu homeostasis is critical for the survival and virulence of fungal pathogens. Cu homeostasis has been extensively studied in mammals, bacteria, and yeast, but it has not yet been well documented in filamentous fungi. In the present work, we investigated Cu tolerance in the filamentous fungus Fusarium oxysporum by analysing the Cu transporter coding gene crpF , previously studied in Aspergillus fumigatus . The expression studies demonstrated that crpF is upregulated in the presence of Cu and its deletion leads to severe sensitivity to low levels of CuSO 4 in F. oxysporum . Targeted deletion of crpF did not significantly alter the resistance of the fungus to macrophage killing, nor its pathogenic behaviour on the tomato plants. However, the targeted deletion mutant Δ crpF showed increased virulence in a murine model of systemic infection compared to wild-type strain (wt).

The increasing number of infections by species of Mucorales and their high mortality constitute an important concern for public health. This study aims to decipher the genetic basis of Mucor circinelloides pathogenicity, which displays virulence in a strain dependent manner. Assuming that genetic differences between strains may be linked to different pathotypes, we have conducted a study to explore genes responsible for virulence in M. circinelloides by whole genome sequencing of the avirulent strain NRRL3631 and comparison with the virulent strain CBS277.49. This genome analysis revealed 773 truncated, discontiguous and absent genes in the NRRL3631 strain. We also examined phenotypic traits resulting in reduced heat stress tolerance, chitosan content and lower susceptibility to toxic compounds (calcofluor white and sodium dodecyl sulphate) in the virulent strain, suggesting the influence of cell wall on pathogenesis. Based on these results, we focused on studying extracellular protein-coding genes by gene deletion and further pathotype characterization of mutants in murine models of pulmonary and systemic infection. Deletion of gene ID112092, which codes for a hypothetical extracellular protein of unknown function, resulted in significant reduction of virulence. Although pathogenesis is a multifactorial process, these findings highlight the crucial role of surface and secreted proteins in M. circinelloides virulence and should promote further studies of other differential genes.