An Iron-Mimicking, Trojan Horse-Entering Fungi—Has the Time Come for Molecular Imaging of Fungal Infections?

1. Hayes GE, Denning DW (2013) Frequency, diagnosis and management of fungal respiratory infections. Curr Opin Pulm Med 19: 259–265. doi: 10.1097/MCP.0b013e32835f1ad1 23411576

2. Pfaller MA, Diekema DJ (2010) Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36: 1–53. doi: 10.3109/10408410903241444 20088682

3. Steinbach WJ (2013) Are we there yet? Recent progress in the molecular diagnosis and novel antifungal targeting of Aspergillus fumigatus and invasive aspergillosis. PLoS Pathog 9: e1003642. doi: 10.1371/journal.ppat.1003642 24204250

4. Maertens JA, Nucci M, Donnelly JP (2012) The role of antifungal treatment in hematology. Haematologica 97: 325–327. doi: 10.3324/haematol.2012.061952 22383742

5. Lin M, Shon IH, Lin P (2010) Positron emission tomography: current status and future challenges. Intern Med J 40: 19–29. doi: 10.1111/j.1445-5994.2009.02072.x 20561362

6. Haubner R (2010) PET radiopharmaceuticals in radiation treatment planning—synthesis and biological characteristics. Radiother Oncol 96: 280–287. doi: 10.1016/j.radonc.2010.07.022 20724013

7. Wadsak W, Mitterhauser M (2010) Basics and principles of radiopharmaceuticals for PET/CT. Eur J Radiol 73: 461–469. doi: 10.1016/j.ejrad.2009.12.022 20181453

8. Signore A, Glaudemans AW (2011) The molecular imaging approach to image infections and inflammation by nuclear medicine techniques. Ann Nucl Med 25: 681–700. doi: 10.1007/s12149-011-0521-z 21837469

9. Lupetti A, de Boer MG, Erba P, Campa M, Nibbering PH (2011) Radiotracers for fungal infection imaging. Med Mycol 49 Suppl 1: S62–69. doi: 10.3109/13693786.2010.508188 20795767

10. Kwon-Chung KJ, Sugui JA (2013) Aspergillus fumigatus--what makes the species a ubiquitous human fungal pathogen? PLoS Pathog 9: e1003743. doi: 10.1371/journal.ppat.1003743 24348239

11. Wang Y, Chen L, Liu X, Cheng D, Liu G, et al. (2013) Detection of Aspergillus fumigatus pulmonary fungal infections in mice with (99m)Tc-labeled MORF oligomers targeting ribosomal RNA. Nucl Med Biol 40: 89–96. doi: 10.1016/j.nucmedbio.2012.10.001 23142409

12. Yang Z, Kontoyiannis DP, Wen X, Xiong C, Zhang R, et al. (2009) Gamma scintigraphy imaging of murine invasive pulmonary aspergillosis with a (111)In-labeled cyclic peptide. Nucl Med Biol 36: 259–266. doi: 10.1016/j.nucmedbio.2008.12.004 19324271

13. Thornton CR (2014) Breaking the mould—novel diagnostic and therapeutic strategies for invasive pulmonary aspergillosis in the immune deficient patient. Expert Rev Clin Immunol 10: 771–780. doi: 10.1586/1744666X.2014.904747 24689528

14. Cassat JE, Skaar EP (2013) Iron in infection and immunity. Cell Host Microbe 13: 509–519. doi: 10.1016/j.chom.2013.04.010 23684303

15. Schrettl M, Bignell E, Kragl C, Joechl C, Rogers T, et al. (2004) Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence. J Exp Med 200: 1213–1219. doi: 10.1084/jem.20041242 15504822

16. McDonagh A, Fedorova ND, Crabtree J, Yu Y, Kim S, et al. (2008) Sub-telomere directed gene expression during initiation of invasive aspergillosis. PLoS Pathog 4: e1000154. doi: 10.1371/journal.ppat.1000154 18787699

17. Schrettl M, Kim HS, Eisendle M, Kragl C, Nierman WC, et al. (2008) SreA-mediated iron regulation in Aspergillus fumigatus. Mol Microbiol 70: 27–43. doi: 10.1111/j.1365-2958.2008.06376.x 18721228

18. Hider RC, Kong X (2010) Chemistry and biology of siderophores. Nat Prod Rep 27: 637–657. doi: 10.1039/b906679a 20376388

19. Hissen AH, Moore MM (2005) Site-specific rate constants for iron acquisition from transferrin by the Aspergillus fumigatus siderophores N′,N′′,N′′′-triacetylfusarinine C and ferricrocin. J Biol Inorg Chem 10: 211–220. doi: 10.1007/s00775-005-0630-z 15770504

20. Haas H (2012) Iron—A Key Nexus in the Virulence of Aspergillus fumigatus. Front Microbiol 3: 28. doi: 10.3389/fmicb.2012.00028 22347220

21. Schrettl M, Bignell E, Kragl C, Sabiha Y, Loss O, et al. (2007) Distinct Roles for Intra- and Extracellular Siderophores during Aspergillus fumigatus Infection. PLoS Pathog 3: e128. doi: 10.1371/journal.ppat.0030128

22. Yasmin S, Alcazar-Fuoli L, Grundlinger M, Puempel T, Cairns T, et al. (2012) Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus. Proc Natl Acad Sci U S A 109: E497–504. doi: 10.1073/pnas.1106399108 22106303

23. Haas H, Eisendle M, Turgeon BG (2008) Siderophores in fungal physiology and virulence. Annu Rev Phytopathol 46: 149–187. doi: 10.1146/annurev.phyto.45.062806.094338 18680426

24. Raymond-Bouchard I, Carroll CS, Nesbitt JR, Henry KA, Pinto LJ, et al. (2012) Structural requirements for the activity of the MirB ferrisiderophore transporter of Aspergillus fumigatus. Eukaryot Cell 11: 1333–1344. doi: 10.1128/EC.00159-12 22903978

25. Haas H, Schoeser M, Lesuisse E, Ernst JF, Parson W, et al. (2003) Characterization of the Aspergillus nidulans transporters for the siderophores enterobactin and triacetylfusarinine C. Biochem J 371: 505–513. doi: 10.1042/BJ20021685 12487628

26. Kragl C, Schrettl M, Abt B, Sarg B, Lindner HH, et al. (2007) EstB-mediated hydrolysis of the siderophore triacetylfusarinine C optimizes iron uptake of Aspergillus fumigatus. Eukaryot Cell 6: 1278–1285. doi: 10.1128/EC.00066-07 17586718

27. Grundlinger M, Gsaller F, Schrettl M, Lindner H, Haas H (2013) Aspergillus fumigatus SidJ mediates intracellular siderophore hydrolysis. Appl Environ Microbiol 79: 7534–7536. doi: 10.1128/AEM.01285-13 24038704

28. Gsaller F, Eisendle M, Lechner BE, Schrettl M, Lindner H, et al. (2012) The interplay between vacuolar and siderophore-mediated iron storage in Aspergillus fumigatus. Metallomics 4: 1262–1270. doi: 10.1039/c2mt20179h 23151814

29. Philpott CC (2006) Iron uptake in fungi: a system for every source. Biochim Biophys Acta 1763: 636–645. doi: 10.1016/j.bbamcr.2006.05.008 16806534

30. Petrik M, Haas H, Schrettl M, Helbok A, Blatzer M, et al. (2012) In vitro and in vivo evaluation of selected 68Ga-siderophores for infection imaging. Nucl Med Biol 39: 361–369. doi: 10.1016/j.nucmedbio.2011.09.012 22172389

31. Llinas M, Klein MP, Neilands JB (1970) Solution conformation of ferrichrome, a microbial iron transport cyclohexapeptide, as deduced by high resolution proton magnetic resonance. J Mol Biol 52: 399–414. doi: 10.1016/0022-2836(70)90409-2 5492288

32. Emery T, Hoffer PB (1980) Siderophore-mediated mechanism of gallium uptake demonstrated in the microorganism Ustilago sphaerogena. J Nucl Med 21: 935–939. 7420194

33. Velikyan I (2013) Prospective of (6)(8)Ga-radiopharmaceutical development. Theranostics 4: 47–80. doi: 10.7150/thno.7447 24396515

34. Petrik M, Haas H, Dobrozemsky G, Lass-Florl C, Helbok A, et al. (2010) 68Ga-siderophores for PET imaging of invasive pulmonary aspergillosis: proof of principle. J Nucl Med 51: 639–645. doi: 10.2967/jnumed.109.072462 20351354

35. Barona-Gomez F, Wong U, Giannakopulos AE, Derrick PJ, Challis GL (2004) Identification of a cluster of genes that directs desferrioxamine biosynthesis in Streptomyces coelicolor M145. J Am Chem Soc 126: 16282–16283. doi: 10.1021/ja045774k 15600304

36. Petrik M, Franssen GM, Haas H, Laverman P, Hortnagl C, et al. (2012) Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging. Eur J Nucl Med Mol Imaging 39: 1175–1183. doi: 10.1007/s00259-012-2110-3 22526953

37. Sia AK, Allred BE, Raymond KN (2013) Siderocalins: Siderophore binding proteins evolved for primary pathogen host defense. Curr Opin Chem Biol 17: 150–157. doi: 10.1016/j.cbpa.2012.11.014 23265976

38. Petrik M, Haas H, Laverman P, Schrettl M, Franssen GM, et al. (2014) 68Ga-triacetylfusarinine C and 68Ga-ferrioxamine E for Aspergillus infection imaging: uptake specificity in various microorganisms. Mol Imaging Biol 16: 102–108. doi: 10.1007/s11307-013-0654-7 23818006