. Recent estimates indicate that meningoencephalitis caused by the pathogenic fungus Cryptococcus neoformans is responsible 15% of deaths in AIDS patients. Along with other fungal pathogens, C. neoformans is therefore a major threat to the 37 million people worldwide living with HIV. A complex of related species originally designated Cryptococcus gattii has recently emerged as a primary pathogen of immunocompetent people. The long-term goal of our research program is to acquire knowledge that will lead to new strategies to combat cryptococcal infections. In particular, we are working to acquire a detailed understanding of the factors required for fungi to proliferate in vertebrate hosts. In particular, we seek to identify new targets for therapy. Our focus is on iron as an essential nutrient for pathogen proliferation and an important indicator of the host environment. Iron is especially important because mammals actively withhold iron from pathogens through a process called nutritional immunity. Pathogens must therefore be able to successfully compete for iron in order to cause disease. We have shown that iron influences the growth of C. neoformans and also the size of the polysaccharide capsule that is the major virulence factor. Our efforts have focused on characterizing the mechanisms of iron sensing and exploiting the regulatory information to identify targets required for iron acquisition. The first specific aim is to characterize the monothiol glutaredoxin Grx4 as a key sensor of iron availability. Grx4 interacts with the iron regulator Cir1 and the proteins regulate iron homeostasis and the expression of virulence factors. We seek to understand the mechanisms of iron sensing and how the iron signal influences gene expression. A second specific aim will investigate the interaction of Grx4 with a network of transcription factors. Two strong candidates have been identified (HapX and Gat201) and the interactions and regulatory influences of these proteins with Grx4 will be characterized. A final specific aim is based on highly productive genetic screens that identified components of the intracellular machinery for heme trafficking. Mutants lacking trafficking functions for heme acquisition will be constructed and tested in mouse inhalation models of cryptococcosis. Additionally, a heme sensor has been developed to detect heme availability in trafficking mutants in culture and in cryptococcal cells during proliferation in different host tissue locations. Overall, these studies will provide a comprehensive view the integration of iron sensing with the regulation of uptake strategies that are critical during cryptococcosis. !
. The relevance of this project comes from the pressing need to control fungal infections in humans with impaired immune systems. In particular, the >37 million 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 ability of fungal pathogens to acquire iron as a vital nutrient during infection. !
|Rizzo, Juliana; Colombo, Ana C; Zamith-Miranda, Daniel et al. (2018) The putative flippase Apt1 is required for intracellular membrane architecture and biosynthesis of polysaccharide and lipids in Cryptococcus neoformans. Biochim Biophys Acta Mol Cell Res 1865:532-541|
|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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