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Mycopathologia

, Volume 178, Issue 5–6, pp 387–393 | Cite as

Neutrophil Responses to Aspergillosis: New Roles for Old Players

  • Cristina Cunha
  • Oliver Kurzai
  • Jürgen Löffler
  • Franco Aversa
  • Luigina Romani
  • Agostinho Carvalho
Article

Abstract

Neutrophils are professional phagocytic cells that play a crucial role in innate immunity. Through an assortment of antifungal effector mechanisms, neutrophils are essential in controlling the early stages of fungal infection. These mechanisms range from the production of reactive oxygen intermediates and release of antimicrobial enzymes to the formation of complex extracellular traps that aid in the elimination of the fungus. Their importance in antifungal immunity is supported by the extreme susceptibility to infection of patients with primary (e.g., chronic granulomatous disease) or acquired (e.g., undergoing immunosuppressive therapy) neutrophil deficiency. More recently, common genetic variants affecting neutrophil antifungal capacity have also been disclosed as major risk factors for aspergillosis in conditions of generalized immune deficiency. The present review revisits the role of neutrophils in the host response against Aspergillus and highlights the consequences of their deficiency in susceptibility to aspergillosis.

Keywords

Aspergillosis Neutrophils Innate immunity Antifungal effector function 

Notes

Acknowledgments

This work was supported by a Research Grant from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Cristina Cunha was supported by the Fundação para a Ciência e Tecnologia, Portugal (contract SFRH/BPD/96176/2013).

References

  1. 1.
    Segal BH. Aspergillosis. N Engl J Med. 2009;360(18):1870–84.PubMedCrossRefGoogle Scholar
  2. 2.
    Mircescu MM, Lipuma L, van Rooijen N, Pamer EG, Hohl TM. Essential role for neutrophils but not alveolar macrophages at early time points following Aspergillus fumigatus infection. J Infect Dis. 2009;200(4):647–56.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Romani L, Fallarino F, De Luca A, Montagnoli C, D’Angelo C, Zelante T, et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature. 2008;451(7175):211–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Bruns S, Kniemeyer O, Hasenberg M, Aimanianda V, Nietzsche S, Thywissen A, et al. Production of extracellular traps against Aspergillus fumigatus in vitro and in infected lung tissue is dependent on invading neutrophils and influenced by hydrophobin RodA. PLoS Pathog. 2010;6(4):e1000873.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Mehrad B, Strieter RM, Moore TA, Tsai WC, Lira SA, Standiford TJ. CXC chemokine receptor-2 ligands are necessary components of neutrophil-mediated host defense in invasive pulmonary aspergillosis. J Immunol. 1999;163(11):6086–94.PubMedGoogle Scholar
  6. 6.
    Edwards MR, Mukaida N, Johnson M, Johnston SL. IL-1beta induces IL-8 in bronchial cells via NF-kappaB and NF-IL6 transcription factors and can be suppressed by glucocorticoids. Pulm Pharmacol Ther. 2005;18(5):337–45.PubMedCrossRefGoogle Scholar
  7. 7.
    Espinosa V, Jhingran A, Dutta O, Kasahara S, Donnelly R, Du P, et al. Inflammatory monocytes orchestrate innate antifungal immunity in the lung. PLoS Pathog. 2014;10(2):e1003940.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Romani L. Immunity to fungal infections. Nat Rev Immunol. 2011;11(4):275–88.PubMedCrossRefGoogle Scholar
  9. 9.
    Hasenberg M, Behnsen J, Krappmann S, Brakhage A, Gunzer M. Phagocyte responses towards Aspergillus fumigatus. Int J Med Microbiol. 2011;301(5):436–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Drewniak A, Gazendam RP, Tool AT, van Houdt M, Jansen MH, van Hamme JL, et al. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood. 2013;121(13):2385–92.PubMedCrossRefGoogle Scholar
  11. 11.
    Bellocchio S, Moretti S, Perruccio K, Fallarino F, Bozza S, Montagnoli C, et al. TLRs govern neutrophil activity in aspergillosis. J Immunol. 2004;173(12):7406–15.PubMedCrossRefGoogle Scholar
  12. 12.
    Scapini P, Lapinet-Vera JA, Gasperini S, Calzetti F, Bazzoni F, Cassatella MA. The neutrophil as a cellular source of chemokines. Immunol Rev. 2000;177:195–203.PubMedCrossRefGoogle Scholar
  13. 13.
    Braedel S, Radsak M, Einsele H, Latge JP, Michan A, Loeffler J, et al. Aspergillus fumigatus antigens activate innate immune cells via toll-like receptors 2 and 4. Br J Haematol. 2004;125(3):392–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Taylor PR, Roy S, Leal SM Jr, Sun Y, Howell SJ, Cobb BA, et al. Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORgammat and dectin-2. Nat Immunol. 2014;15(2):143–51.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Aimanianda V, Bayry J, Bozza S, Kniemeyer O, Perruccio K, Elluru SR, et al. Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature. 2009;460(7259):1117–21.PubMedCrossRefGoogle Scholar
  16. 16.
    Carrion Sde J, Leal SM, Jr., Ghannoum MA, Aimanianda V, Latge JP, Pearlman E. The RodA hydrophobin on Aspergillus fumigatus spores masks dectin-1- and dectin-2-dependent responses and enhances fungal survival in vivo. J Immunol. 2013;191(5):2581-8.Google Scholar
  17. 17.
    Lee MJ, Gravelat FN, Cerone RP, Baptista SD, Campoli PV, Choe SI, et al. Overlapping and distinct roles of Aspergillus fumigatus UDP-glucose 4-epimerases in galactose metabolism and the synthesis of galactose-containing cell wall polysaccharides. J Biol Chem. 2014;289(3):1243–56.PubMedCrossRefGoogle Scholar
  18. 18.
    Fontaine T, Delangle A, Simenel C, Coddeville B, van Vliet SJ, van Kooyk Y, et al. Galactosaminogalactan, a new immunosuppressive polysaccharide of Aspergillus fumigatus. PLoS Pathog. 2011;7(11):e1002372.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Gravelat FN, Beauvais A, Liu H, Lee MJ, Snarr BD, Chen D, et al. Aspergillus galactosaminogalactan mediates adherence to host constituents and conceals hyphal beta-glucan from the immune system. PLoS Pathog. 2013;9(8):e1003575.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Gresnigt MS, Bozza S, Becker KL, Joosten LA, Abdollahi-Roodsaz S, van der Berg WB, et al. A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1 receptor antagonist. PLoS Pathog. 2014;10(3):e1003936.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Garlanda C, Hirsch E, Bozza S, Salustri A, De Acetis M, Nota R, et al. Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature. 2002;420(6912):182–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Jaillon S, Peri G, Delneste Y, Fremaux I, Doni A, Moalli F, et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med. 2007;204(4):793–804.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Moalli F, Doni A, Deban L, Zelante T, Zagarella S, Bottazzi B, et al. Role of complement and Fc{gamma} receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus. Blood. 2010;116(24):5170–80.PubMedCrossRefGoogle Scholar
  24. 24.
    Cunha C, Aversa F, Lacerda JF, Busca A, Kurzai O, Grube M, et al. Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med. 2014;370(5):421–32.PubMedCrossRefGoogle Scholar
  25. 25.
    Behnsen J, Hartmann A, Schmaler J, Gehrke A, Brakhage AA, Zipfel PF. The opportunistic human pathogenic fungus Aspergillus fumigatus evades the host complement system. Infect Immun. 2008;76(2):820–7.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Luo S, Skerka C, Kurzai O, Zipfel PF. Complement and innate immune evasion strategies of the human pathogenic fungus Candida albicans. Mol Immunol. 2013;56(3):161–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Bouzani M, Ok M, McCormick A, Ebel F, Kurzai O, Morton CO, et al. Human NK cells display important antifungal activity against Aspergillus fumigatus, which is directly mediated by IFN-gamma release. J Immunol. 2011;187(3):1369–76.PubMedCrossRefGoogle Scholar
  28. 28.
    Schmidt S, Tramsen L, Hanisch M, Latge JP, Huenecke S, Koehl U, et al. Human natural killer cells exhibit direct activity against Aspergillus fumigatus hyphae, but not against resting conidia. J Infect Dis. 2011;203(3):430–5.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Voigt J, Hunniger K, Bouzani M, Jacobsen ID, Barz D, Hube B, et al. Human natural killer cells acting as phagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity. J Infect Dis. 2014;209(4):616–26.PubMedCrossRefGoogle Scholar
  30. 30.
    Robinet P, Baychelier F, Fontaine T, Picard C, Debre P, Vieillard V, et al. A polysaccharide virulence factor of a human fungal pathogen induces neutrophil apoptosis via NK cells. J Immunol. 2014;192(11):5332–42.PubMedCrossRefGoogle Scholar
  31. 31.
    Li SS, Kyei SK, Timm-McCann M, Ogbomo H, Jones GJ, Shi M, et al. The NK receptor NKp30 mediates direct fungal recognition and killing and is diminished in NK cells from HIV-infected patients. Cell Host Microbe. 2013;14(4):387–97.PubMedCrossRefGoogle Scholar
  32. 32.
    Vinh DC. Insights into human antifungal immunity from primary immunodeficiencies. Lancet Infect Dis. 2011;11(10):780–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Bonnett CR, Cornish EJ, Harmsen AG, Burritt JB. Early neutrophil recruitment and aggregation in the murine lung inhibit germination of Aspergillus fumigatus conidia. Infect Immun. 2006;74(12):6528–39.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Reeves EP, Lu H, Jacobs HL, Messina CG, Bolsover S, Gabella G, et al. Killing activity of neutrophils is mediated through activation of proteases by K + flux. Nature. 2002;416(6878):291–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Segal AW. How neutrophils kill microbes. Ann Rev Immunol. 2005;23:197–223.CrossRefGoogle Scholar
  36. 36.
    Klebanoff SJ. Myeloperoxidase: friend and foe. J Leuk Biol. 2005;77(5):598–625.CrossRefGoogle Scholar
  37. 37.
    Aratani Y, Kura F, Watanabe H, Akagawa H, Takano Y, Suzuki K, et al. Relative contributions of myeloperoxidase and NADPH-oxidase to the early host defense against pulmonary infections with Candida albicans and Aspergillus fumigatus. Med Mycol. 2002;40(6):557–63.PubMedCrossRefGoogle Scholar
  38. 38.
    Tapper H. The secretion of preformed granules by macrophages and neutrophils. J Leuk Biol. 1996;59(5):613–22.Google Scholar
  39. 39.
    Ibrahim-Granet O, Jouvion G, Hohl TM, Droin-Bergere S, Philippart F, Kim OY, et al. In vivo bioluminescence imaging and histopathopathologic analysis reveal distinct roles for resident and recruited immune effector cells in defense against invasive aspergillosis. BMC Microbiol. 2010;10:105.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Tkalcevic J, Novelli M, Phylactides M, Iredale JP, Segal AW, Roes J. Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity. 2000;12(2):201–10.PubMedCrossRefGoogle Scholar
  41. 41.
    Vethanayagam RR, Almyroudis NG, Grimm MJ, Lewandowski DC, Pham CT, Blackwell TS, et al. Role of NADPH oxidase versus neutrophil proteases in antimicrobial host defense. PLoS ONE. 2011;6(12):e28149.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Legrand D. Lactoferrin, a key molecule in immune and inflammatory processes. Biochem Cell Biol. 2012;90(3):252–68.PubMedCrossRefGoogle Scholar
  43. 43.
    Zarember KA, Sugui JA, Chang YC, Kwon-Chung KJ, Gallin JI. Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion. J Immunol. 2007;178(10):6367–73.PubMedCrossRefGoogle Scholar
  44. 44.
    Leal SM Jr, Roy S, Vareechon C, Carrion S, Clark H, Lopez-Berges MS, et al. Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum. PLoS Pathog. 2013;9(7):e1003436.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5.PubMedCrossRefGoogle Scholar
  46. 46.
    Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231–41.Google Scholar
  47. 47.
    Rohm M, Grimm MJ, D’Auria AC, Almyroudis NG, Segal BH, Urban CF. NADPH oxidase promotes neutrophil extracellular trap formation in pulmonary aspergillosis. Infect Immun. 2014;82(5):1766–77.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Bianchi M, Hakkim A, Brinkmann V, Siler U, Seger RA, Zychlinsky A, et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009;114(13):2619–22.Google Scholar
  49. 49.
    von Kockritz-Blickwede M, Chow OA, Nizet V. Fetal calf serum contains heat-stable nucleases that degrade neutrophil extracellular traps. Blood. 2009;114(25):5245–6.CrossRefGoogle Scholar
  50. 50.
    Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009;5(10):e1000639.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Vinh DC, Sugui JA, Hsu AP, Freeman AF, Holland SM. Invasive fungal disease in autosomal-dominant hyper-IgE syndrome. J Allergy Clin Immunol. 2010;125(6):1389–90.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Cunha C, Aversa F, Romani L, Carvalho A. Human genetic susceptibility to invasive aspergillosis. PLoS Pathog. 2013;9(8):e1003434.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Cunha C, Carvalho A. Host genetics and invasive fungal diseases: towards improved diagnosis and therapy? Expert Rev Anti Infect Ther. 2012;10(3):257–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Cristina Cunha
    • 1
    • 2
  • Oliver Kurzai
    • 3
  • Jürgen Löffler
    • 4
  • Franco Aversa
    • 5
  • Luigina Romani
    • 6
  • Agostinho Carvalho
    • 1
    • 2
  1. 1.Life and Health Sciences Research Institute (ICVS), School of Health SciencesUniversity of MinhoBragaPortugal
  2. 2.ICVS/3B’s – PT Government Associate LaboratoryBraga/GuimarãesPortugal
  3. 3.Septomics Research Centre, Friedrich-Schiller-University and Leibniz-Institute for Natural Products Research and Infection BiologyHans-Knöll-InstituteJenaGermany
  4. 4.Medizinische Klinik und Poliklinik IIUniversitätsklinikum WürzburgWürzburgGermany
  5. 5.Department of Clinical and Experimental MedicineUniversity of ParmaParmaItaly
  6. 6.Department of Experimental MedicineUniversity of PerugiaPerugiaItaly

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