Metals in fungal virulence

Abstract

Metals are essential for life, and they play a central role in the struggle between infecting microbes and their hosts. In fact, an important aspect of microbial pathogenesis is the ‘nutritional immunity’, in which metals are actively restricted (or, in an extended definition of the term, locally enriched) by the host to hinder microbial growth and virulence. Consequently, fungi have evolved often complex regulatory networks, uptake and detoxification systems for essential metals such as iron, zinc, copper, nickel and manganese. These systems often differ fundamentally from their bacterial counterparts, but even within the fungal pathogens we can find common and unique solutions to maintain metal homeostasis. Thus, we here compare the common and species-specific mechanisms used for different metals among different fungal species—focusing on important human pathogens such as Candida albicans, Aspergillus fumigatus or Cryptococcus neoformans, but also looking at model fungi such as Saccharomyces cerevisiae or A. nidulans as well-studied examples for the underlying principles. These direct comparisons of our current knowledge reveal that we have a good understanding how model fungal pathogens take up iron or zinc, but that much is still to learn about other metals and specific adaptations of individual species—not the least to exploit this knowledge for new antifungal strategies.

Eukaryotic transposable elements as “cargo carriers”: the forging of metal resistance in the fungusPaecilomyces variotii

“…Some fungi are able to accumulate metals to high concentrations, making such fungi dangerous for human consumption 2,3 , allowing bioremediation of contaminated sites 4 or concentrating valuable metals for extraction 5 . Zinc and copper play essential roles in many cellular functions and are often important in fungal virulence 6 . However, at high concentrations these metals can also be toxic; for example, copper-based molecules are frequently used as fungicides in agriculture.…”

Role of Nickel in Microbial Pathogenesis

“…In contrast to metals such as copper, zinc, and iron, little is known of the roles of nickel in fungal pathogenesis. Still, ureases play important roles in fungal pathogens, for example in C. neoformans and in C. immitis (Table 1) [140]. In C. neoformans (responsible for human meningoencephalitis), Ni-urease is an important factor for brain invasion, as shown in several independent studies [18,19].…”

“…In C. posadasii, the causative agent of San Joaqin Valley fever, the extracellular ammonia generated (by urease) at sites of pulmonary infection contributes to severity of the respiratory disease [23], and urease mutants are less virulent in a mouse intranasal challenge [22]. A nickel permease homolog is present in the Aspergillus fumigatus genome, but the role it plays is not known [140]. It is worth noting, however, that many fungal pathogens apparently have no need for nickel, relying instead on a non-Ni, biotin-requiring urease to metabolize urea.…”

Environmental Factors That Contribute to the Maintenance of Cryptococcus neoformans Pathogenesis

“…This (acidic environment), however, does not seem to inhibit the growth of these cells, which suggests that C. neoformans is well adapted to low pH [57]. In part, this adaptation to acidic pH is beneficial to cryptococcal cells in that it allows them access to iron [106,107], which is inaccessible at neutral pH due to iron being bound to transferrin [108].…”