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Zinc Acquisition: A Key Aspect in Aspergillus fumigatus Virulence

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Abstract

Zinc is an essential micronutrient required for the growth of all microorganisms. To grow in the lungs of a susceptible patient Aspergillus fumigatus must obtain zinc from the surrounding tissues. The concentration of Zn2+ ions in living tissues is much lower than that required for optimal fungal growth in vitro because most of them are tightly bound to proteins at the physiological pH. However, A. fumigatus has several zinc transporters (ZrfA, ZrfB and ZrfC) that enable it to uptake zinc efficiently under the extreme zinc-limiting conditions provided by a susceptible host. The ZafA transcriptional regulator induces the expression of these transporters and is essential for virulence. ZrfC is required for fungal growth within the host tissues, whereas ZrfA and ZrfB play an accessory role. The zinc-scavenging capacity of ZrfC relies on its unusually long N-terminus. In addition, ZrfC also enables A. fumigatus to overcome the inhibitory effect of calprotectin, which is an antimicrobial Zn/Mn-chelating protein synthesized in high amounts by neutrophils, even in immunosuppressed non-leucopenic animals. In summary, the regulation of zinc homeostasis and zinc acquisition could be promising targets for the discovery and development of a new generation of antifungals for the treatment of invasive pulmonary aspergillosis.

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References

  1. Andreini C, Bertini I, Cavallaro G, Holliday GL, Thornton JM. Metal ions in biological catalysis: from enzyme databases to general principles. J Biol Inorg Chem. 2008;13:1205–18.

    Article  CAS  PubMed  Google Scholar 

  2. Andreini C, Banci L, Bertini I, Rosato A. Counting the zinc-proteins encoded in the human genome. J Proteome Res. 2006;5:196–201.

    Article  CAS  PubMed  Google Scholar 

  3. Outten CE, O’Halloran TV. Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science. 2001;292:2488–92.

    Article  CAS  PubMed  Google Scholar 

  4. Casadevall A, Pirofski L. Host-pathogen interactions: the attributes of virulence. J Infect Dis. 2001;184:337–44.

    Article  CAS  PubMed  Google Scholar 

  5. Gaither LA, Eide DJ. Eukaryotic zinc transporters and their regulation. Biometals. 2001;14:251–70.

    Article  CAS  PubMed  Google Scholar 

  6. Sinclair SA, Kramer U. The zinc homeostasis network of land plants. Biochim Biophys Acta. 2012;1823:1553–67.

    Article  CAS  PubMed  Google Scholar 

  7. Song WY, Hortensteiner S, Tomioka R, Lee Y, Martinoia E. Common functions or only phylogenetically related? The large family of PLAC8 motif-containing/PCR genes. Mol Cells. 2011;31:1–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Nevo Y, Nelson N. The NRAMP family of metal-ion transporters. Biochim Biophys Acta. 2006;1763:609–20.

    Article  CAS  PubMed  Google Scholar 

  9. Axelsen KB, Palmgren MG. Inventory of the superfamily of P-type ion pumps in Arabidopsis. Plant Physiol. 2001;126:696–706.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Kovalchuk A, Driessen AJ. Phylogenetic analysis of fungal ABC transporters. BMC Genom. 2010;11:177.

    Article  Google Scholar 

  11. Ricachenevsky FK, Sperotto RA, Menguer PK, Sperb ER, Lopes KL, Fett JP. ZINC-INDUCED FACILITATOR-LIKE family in plants: lineage-specific expansion in monocotyledons and conserved genomic and expression features among rice (Oryza sativa) paralogs. BMC Plant Biol. 2011;11:20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Gomolplitinant KM, Saier MH Jr. Evolution of the oligopeptide transporter family. J Membr Biol. 2011;240:89–110.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Eide DJ. Homeostatic and adaptive responses to zinc deficiency in Saccharomyces cerevisiae. J Biol Chem. 2009;284:18565–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Amich J, Leal F, Calera JA. Repression of the acid ZrfA/ZrfB zinc-uptake system of Aspergillus fumigatus mediated by PacC under neutral, zinc-limiting conditions. Int Microbiol. 2009;12:39–47.

    CAS  PubMed  Google Scholar 

  15. Amich J, Vicentefranqueira R, Leal F, Calera JA. Aspergillus fumigatus survival in alkaline and extreme zinc-limiting environments relies on the induction of a zinc homeostasis system encoded by the zrfC and aspf2 genes. Eukaryot Cell. 2010;9:424–37.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Vicentefranqueira R, Moreno MA, Leal F, Calera JA. The zrfA and zrfB genes of Aspergillus fumigatus encode the zinc transporter proteins of a zinc uptake system induced in an acid, zinc-depleted environment. Eukaryot Cell. 2005;4:837–48.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Yasmin S, Abt B, Schrettl M, Moussa TA, Werner ER, Haas H. The interplay between iron and zinc metabolism in Aspergillus fumigatus. Fungal Genet Biol. 2009;46:707–13.

    Article  CAS  PubMed  Google Scholar 

  18. Conklin DS, McMaster JA, Culbertson MR, Kung C. COT1, a gene involved in cobalt accumulation in Saccharomyces cerevisiae. Mol Cell Biol. 1992;12:3678–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Miyabe S, Izawa S, Inoue Y. Expression of ZRC1 coding for suppressor of zinc toxicity is induced by zinc-starvation stress in Zap1-dependent fashion in Saccharomyces cerevisiae. Biochem Biophys Res Commun. 2000;276:879–84.

    Article  CAS  PubMed  Google Scholar 

  20. Lu M, Chai J, Fu D. Structural basis for autoregulation of the zinc transporter YiiP. Nat Struct Mol Biol. 2009;16:1063–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Delhaize E, Gruber BD, Pittman JK, White RG, Leung H, Miao Y, Jiang L, Ryan PR, Richardson AE. A role for the AtMTP11 gene of Arabidopsis in manganese transport and tolerance. Plant J. 2007;51:198–210.

    Article  CAS  PubMed  Google Scholar 

  22. Porcheron G, Garenaux A, Proulx J, Sabri M, Dozois CM. Iron, copper, zinc, and manganese transport and regulation in pathogenic Enterobacteria: correlations between strains, site of infection and the relative importance of the different metal transport systems for virulence. Front Cell Infect Microbiol. 2013;3:90.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Shafeeq S, Kuipers OP, Kloosterman TG. The role of zinc in the interplay between pathogenic streptococci and their hosts. Mol Microbiol. 2013;88:1047–57.

    Article  CAS  PubMed  Google Scholar 

  24. Haas CE, Rodionov DA, Kropat J, Malasarn D, Merchant SS, de Crecy-Lagard V. A subset of the diverse COG0523 family of putative metal chaperones is linked to zinc homeostasis in all kingdoms of life. BMC Genom. 2009;10:470.

    Article  Google Scholar 

  25. Moreno MA, Ibrahim-Granet O, Vicentefranqueira R, Amich J, Ave P, Leal F, Latge JP, Calera JA. The regulation of zinc homeostasis by the ZafA transcriptional activator is essential for Aspergillus fumigatus virulence. Mol Microbiol. 2007;64:1182–97.

    Article  CAS  PubMed  Google Scholar 

  26. Caddick MX, Brownlee AG, Arst HN Jr. Regulation of gene expression by pH of the growth medium in Aspergillus nidulans. Mol Gen Genet. 1986;203:346–53.

    Article  CAS  PubMed  Google Scholar 

  27. Matthews TM, Webb C. Saccharomyces. In: Tuite MF, Oliver SG, editors. Culture systems, vol. 4. New York, NY: Plenum Press; 1991. p. 249–89.

    Google Scholar 

  28. Peñalva MA, Tilburn J, Bignell E, Arst HN Jr. Ambient pH gene regulation in fungi: making connections. Trends Microbiol. 2008;16:291–300.

    Article  PubMed  Google Scholar 

  29. Amich J, Vicentefranqueira R, Mellado E, Ruiz-Carmuega A, Leal F, Calera JA. The ZrfC alkaline zinc transporter is required for Aspergillus fumigatus virulence and its growth in the presence of the Zn/Mn-chelating protein calprotectin. Cell Microbiol. 2014;16:548–64.

    Article  CAS  PubMed  Google Scholar 

  30. Iyengar V, Woittiez J. Trace elements in human clinical specimens: evaluation of literature data to identify reference values. Clin Chem. 1988;34:474–81.

    CAS  PubMed  Google Scholar 

  31. Corbin BD, Seeley EH, Raab A, Feldmann J, Miller MR, Torres VJ, Anderson KL, Dattilo BM, Dunman PM, Gerads R, Caprioli RM, Nacken W, Chazin WJ, Skaar EP. Metal chelation and inhibition of bacterial growth in tissue abscesses. Science. 2008;319:962–5.

    Article  CAS  PubMed  Google Scholar 

  32. Sohnle PG, Hahn BL, Santhanagopalan V. Inhibition of Candida albicans growth by calprotectin in the absence of direct contact with the organisms. J Infect Dis. 1996;174:1369–72.

    Article  CAS  PubMed  Google Scholar 

  33. Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, Brinkmann V, Jungblut PR, Zychlinsky A. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009;5:e1000639.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS Jr. Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival. Immunity. 2013;39:697–710.

    Article  CAS  PubMed  Google Scholar 

  35. Botella H, Peyron P, Levillain F, Poincloux R, Poquet Y, Brandli I, Wang C, Tailleux L, Tilleul S, Charriere GM, Waddell SJ, Foti M, Lugo-Villarino G, Gao Q, Maridonneau-Parini I, Butcher PD, Castagnoli PR, Gicquel B, de Chastellier C, Neyrolles O. Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages. Cell Host Microbe. 2011;10:248–59.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev. 2005;18:44–69.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Steinbach WJ, Juvvadi PR, Fortwendel JR, Rogg LE. Newer combination antifungal therapies for invasive aspergillosis. Med Mycol. 2011;49(Suppl 1):S77–81.

    Article  PubMed  Google Scholar 

  38. Steinbach WJ. Are we there yet? Recent progress in the molecular diagnosis and novel antifungal targeting of Aspergillus fumigatus and invasive aspergillosis. PLoS Pathog. 2013;9:e1003642.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Hachem R, Bahna P, Hanna H, Stephens LC, Raad I. EDTA as an adjunct antifungal agent for invasive pulmonary aspergillosis in a rodent model. Antimicrob Agents Chemother. 2006;50:1823–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Ibrahim AS, Gebremariam T, French SW, Edwards JE Jr, Spellberg B. The iron chelator deferasirox enhances liposomal amphotericin B efficacy in treating murine invasive pulmonary aspergillosis. J Antimicrob Chemother. 2010;65:289–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Kontoghiorghes GJ, Kolnagou A, Peng CT, Shah SV, Aessopos A. Safety issues of iron chelation therapy in patients with normal range iron stores including thalassaemia, neurodegenerative, renal and infectious diseases. Expert Opin Drug Saf. 2010;9:201–6.

    Article  CAS  PubMed  Google Scholar 

  42. Leal SM Jr, Roy S, Vareechon C, Carrion S, Clark H, Lopez-Berges MS, diPietro A, Schrettl M, Beckmann N, Redl B, Haas H, Pearlman E. Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum. PLoS Pathog. 2013;9:e1003436.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Zarember KA, Cruz AR, Huang CY, Gallin JI. Antifungal activities of natural and synthetic iron chelators alone and in combination with azole and polyene antibiotics against Aspergillus fumigatus. Antimicrob Agents Chemother. 2009;53:2654–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Cottarel G, Wierzbowski J. Combination drugs, an emerging option for antibacterial therapy. Trends Biotechnol. 2007;25:547–55.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the Spanish Ministry of Economy and Competitiveness for financial support through grants BIO2001-1692, BFU2007-66512, BFU2010-22172 and SAF2013-48382-R.

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  1. Jorge Amich

    Present address: IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II & Universitäts-Kinderklinik, ZEMM - Zinklesweg 10, 97078, Würzburg, Germany

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  1. Instituto de Biología Funcional y Genómica (IBFG) (centro mixto CSIC-Universidad de Salamanca) y Departamento de Microbiología y Genética, Universidad de Salamanca, Edificio IBFG, Lab. P1.10. C/Zacarías González nº 2, 37007, Salamanca, Spain

    Jorge Amich & José Antonio Calera

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Correspondence to José Antonio Calera.

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Amich, J., Calera, J.A. Zinc Acquisition: A Key Aspect in Aspergillus fumigatus Virulence. Mycopathologia 178, 379–385 (2014). https://doi.org/10.1007/s11046-014-9764-2

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