. The pathogenic fungus Cryptococcus neoformans causes life-threatening infections in AIDS patients and therefore poses a major threat to the >34 million people worldwide who are infected with HIV. The related species Cryptococcus gattii has recently emerged as a primary pathogen of immunocompetent people. The long-term goal of this project is to acquire knowledge that will lead to new strategies to combat fungal infections. In particular, we want to establish a detailed understanding of the factors required for pathogen growth in mammalian hosts and identify useful targets for therapy. In this regard, iron availability is a key indicator of the host environment as well as an essential nutrient for pathogen proliferation. In addition, mammals actively withhold iron from pathogens in a process termed nutritional immunity, and pathogens must therefore aggressively compete for iron. Iron is particularly important for the pathogenesis of C. neoformans because the availability of this metal not only influences growth but also the size of the polysaccharide capsule that is the major virulence factor. To fill gaps in our understanding of the mechanisms by which fungal pathogens compete for iron, the first specific aim is to determine the molecular functions of cell surface proteins that support iron acquisition from heme. These proteins each contribute to robust growth on heme and include a secreted mannoprotein that is a candidate heme-binding protein as well as three ferric reductases. A second specific aim will characterize the intracellular machinery for heme trafficking and processing. An insertional mutagenesis screen identified 25 genes in which mutations caused growth defects on heme, and some of these genes encode intracellular trafficking machinery. This result led to the hypothesis that heme is acquired by endocytosis and transported to the vacuole for iron extraction and recycling. Mutants with defects at specific steps in known and candidate transport functions will be constructed and tested for their ability to process heme. A final specific aim will evaluate the role of heme and iron acquisition functions in the virulence of C. neoformans. Mutants lacking combinations of iron acquisition functions will be tested in mouse inhalation models of cryptococcosis and the proliferation of the mutants in macrophages will be examined in the context of different iron sources. These studies will provide a comprehensive view of the relative importance of specific host iron sources and fungal uptake strategies during cryptococcosis. !

Public Health Relevance

of this project comes from the pressing need to control fungal infections in humans with impaired immune systems. In particular, the 34 million or more people infected with HIV have a high chance of succumbing to fungal diseases. The research will specifically examine the potential to control these infections by targeting the abiliy of fungal pathogens to acquire iron as a vital nutrient during infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Duncan, Rory A
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University of British Columbia
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V6 1-Z3
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Attarian, Rodgoun; Hu, Guanggan; Sánchez-León, Eddy et al. (2018) The Monothiol Glutaredoxin Grx4 Regulates Iron Homeostasis and Virulence in Cryptococcus neoformans. MBio 9:
Caza, Mélissa; Hu, Guanggan; Nielson, Erik David et al. (2018) The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans. PLoS Pathog 14:e1007220
Bairwa, Gaurav; Hee Jung, Won; Kronstad, James W (2017) Iron acquisition in fungal pathogens of humans. Metallomics 9:215-227
Hu, Guanggan; Caza, Mélissa; Bakkeren, Erik et al. (2017) A P4-ATPase subunit of the Cdc50 family plays a role in iron acquisition and virulence in Cryptococcus neoformans. Cell Microbiol 19:
Do, Eunsoo; Hu, Guanggan; Caza, Mélissa et al. (2016) The ZIP family zinc transporters support the virulence of Cryptococcus neoformans. Med Mycol 54:605-15
Do, Eunsoo; Park, Minji; Hu, Guanggan et al. (2016) The lysine biosynthetic enzyme Lys4 influences iron metabolism, mitochondrial function and virulence in Cryptococcus neoformans. Biochem Biophys Res Commun 477:706-711
Ding, Hao; Mayer, François L; Sánchez-León, Eddy et al. (2016) Networks of fibers and factors: regulation of capsule formation in Cryptococcus neoformans. F1000Res 5:
Jung, Won Hee; Sham, Anita; White, Rick et al. (2016) Correction: Iron Regulation of the Major Virulence Factors in the AIDS-Associated Pathogen Cryptococcus neoformans. PLoS Biol 14:e1002410
Caza, Mélissa; Hu, Guanggan; Price, Michael et al. (2016) The Zinc Finger Protein Mig1 Regulates Mitochondrial Function and Azole Drug Susceptibility in the Pathogenic Fungus Cryptococcus neoformans. mSphere 1:

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