Iron acquisition in fungal pathogens of humans

Abstract

The devastating infections that fungal pathogens cause in humans are underappreciated relative to viral, bacterial and parasitic diseases. In recent years, the contributions to virulence of reductive iron uptake, siderophore-mediated uptake and heme acquisition have been identified in the best studied and most life-threatening fungal pathogens: Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. In particular, exciting new work illustrates the importance of iron acquisition from heme and hemoglobin in the virulence of pathogenic yeasts. However, the challenge of establishing how these fungi gain access to hemoglobin in blood and to other sources of heme remains to be fully addressed. Recent studies are also expanding our knowledge of iron uptake in less-well studied fungal pathogens, including dimorphic fungi where new information reveals an integration of iron acquisition with morphogenesis and cell-surface properties for adhesion to host cells. Overall, the accumulating information provides opportunities to exploit iron acquisition for antifungal therapy, and new work highlights the development of specific inhibitors of siderophore biosynthesis and metal chelators for therapeutic use alone or in conjunction with existing antifungal drugs. It is clear that iron-related therapies will need to be customized for specific diseases because the emerging view is that fungal pathogens use different combinations of strategies for iron acquisition in the varied niches of vertebrate hosts.

Role of clathrin-mediated endocytosis in the use of heme and hemoglobin by the fungal pathogen Cryptococcus neoformans

“…Heme and hemoglobin serve as important iron sources for the proliferation of C. neoformans (Bairwa et al, ; Jung et al, ). However, very few factors have been identified for heme and hemoglobin uptake and internalisation.…”

“…Sensing and adapting to the availability of metal ions such as iron and copper in the host environment are pivotal for any pathogen to survive and proliferate (Bairwa, Jung, & Kronstad, ; Hood & Skaar, ; Palmer & Skaar, ; Skaar, ). Iron is an essential metal required for several enzymatic and biochemical processes in eukaryotic cells, and the metal plays a crucial role in the virulence of microbial pathogens including C. neoformans (Bairwa et al, ; Jung et al, ; Jung & Kronstad, ; Skaar, ; Weinberg, ). The ability to use host iron sources, such as heme/hemoglobin and transferrin, is advantageous for the growth and survival of C. neoformans inside a vertebrate host (Jung et al, ).…”

A genome scan of diversifying selection in Ophiocordyceps zombie‐ant fungi suggests a role for enterotoxins in co‐evolution and host specificity

“…In addition to carbon and nitrogen, iron uptake is also crucial for pathogen success (Bairwa, Hee Jung, & Kronstad, 2017;Haas, 2012;Sutak, Lesuisse, Tacherzy, & Richardson, 2008). The candidate neuromodulator genes found to be under positive selection included iron-related oxidoreductases.…”

The monothiol glutaredoxin Grx4 interacts with the Cryptococcus iron regulator Cirl and regulates iron homeostasis and virulence in the Cryptococcus neoformans

“…As with other pathogenic microbes, iron sensing and acquisition are important aspects of virulence for C. neoformans (5–8). Iron is important for C. neoformans both as a nutrient and as a signal to regulate the expression of the main virulence factor of the fungus, the polysaccharide capsule (5, 9).…”