Innate Defense against Aspergillus: the Phagocyte

Michel Chignard

doi:10.1128/9781555815523.ch18

Chapter 18 : Innate Defense against Aspergillus: the Phagocyte

Author: Michel Chignard¹

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Affiliations: 1: Unité de Défense innée et Inflammation, Institut Pasteur, and Unité 874, INSERM, 75015 Paris, France

Content Type: Monograph

Publication Year: 2009

Category: Clinical Microbiology; Fungi and Fungal Pathogenesis

Book DOI: 10.1128/9781555815523

Chapter DOI: 10.1128/9781555815523.ch18

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Abstract:

Macrophages and neutrophils are essential components of the innate immune response of the host to infection by microorganisms. Macrophages have three main functions: (i) to take up and kill pathogens by phagocytosis; (ii) to generate a large array of biologically active molecules, including cytokines, chemokines, and lipid mediators, that orchestrate the recruitment of other phagocytes, such as monocytes and neutrophils; and (iii) to present antigens to lymphocytes. The innate immune system is the first line of host defense against pathogens. Macrophages and neutrophils constitute the bulwark of the innate immune system. The macrophages internalize microorganisms via different types of receptors expressed on their surface. These receptors bind pathogen-associated molecular patterns (PAMP) directly or via opsonins. Aspergillus fumigatus is recognized directly, via its carbohydrates, by DC-SIGN and dectin-1. Alveolar macrophages are important for the host defense against A. fumigatus, as demonstrated in a murine model of invasive pulmonary aspergillosis (IPA). As for alveolar macrophages, pathogen recognition is the first important step. Neutrophils express various toll-like receptors (TLRs) but have no TLR3. Alveolar macrophages and neutrophils are clearly of prime importance for combating inhaled A. fumigatus. Indeed, if for any reason these cells are absent or incapacitated, the fungus grows and causes a life threatening infection.

Citation: Chignard M. 2009. Innate Defense against Aspergillus: the Phagocyte, p 229-238. In Latgé J, Steinbach W (ed), Aspergillus fumigatus and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch18

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Innate Defense against Aspergillus: the Phagocyte

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Figure 1.

Role of neutrophils and alveolar macrophages in experimental IPA. Mice were infected intratracheally with 107 (A) or 106 (B) conidia of A. fumigatus. Mice were depleted of neutrophils and macrophages by treatment with vinblastine ( Balloy et al., 2005b ) and chlodronate ( Chignard et al., 2007 ), respectively. (From Chignard et al. [2007] with permission of the publisher.)

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Figure 1.

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Figure 2.

Neutrophil recruitment and chitin concentration in the lung in experimental IPA. Mice were infected intratracheally with 107 conidia of A. fumigatus and BAL was obtained at various time points. Neutrophils were counted and chitin quantified. (Images courtesy of V. Balloy et al. [unpublished data].)

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Figure 2.

References

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1. Aderem, A. 2003. Phagocytosis and the inflammatory response. J. Infect. Dis. 187(Suppl. 2): S340– S345.

2. Aderem, A., and, D. M. Underhill. 1999. Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17: 593– 623.

3. Akira, S.,, S. Uematsu, and, O. Takeuchi. 2006. Pathogen recognition and innate immunity. Cell 124: 783– 801.

4. Aratani, Y.,, F. Kura,, H. Watanabe,, H. Akagawa,, Y. Takano,, K. Suzuki,, M. C. Dinauer,, N. Maeda, and, H. Koyama. 2002. Relative contributions of myeloperoxidase and NADPH-oxidase to the early host defense against pulmonary infections with Candida albicans and Aspergillus fumigatus. Med. Mycol. 40: 557– 563.

5. Balloy, V.,, M. Si-Tahar,, O. Takeuchi,, B. Philippe,, M. A. Nahori,, M. Tanguy,, M. Huerre,, S. Akira,, J. P. Latgé, and, M. Chignard. 2005a. Involvement of toll-like receptor 2 in experimental invasive pulmonary aspergillosis. Infect. Immun. 73: 5420– 5425.

6. Balloy, V.,, M. Huerre,, J. P. Latgé, and, M. Chignard. 2005b. Differences in patterns of infection and inflammation for corticosteroid treatment and chemotherapy in experimental invasive pulmonary aspergillosis. Infect. Immun. 73: 494– 503.

7. Behnsen, J.,, P. Narang,, M. Hasenberg,, F. Gunzer,, U. Bilitewski,, N. Klippel,, M. Rohde,, M. Brock,, A. A. Brakhage, and, M. Gunzer. 2007. Environmental dimensionality controls the interaction of phagocytes with the pathogenic fungi Aspergillus fumigatus and Candida albicans. PLoS Pathog. 3: e13.

8. Bellocchio, S.,, C. Montagnoli,, S. Bozza,, R. Gaziano,, G. Rossi,, S. S. Mambula,, A. Vecchi,, A. Mantovani,, S. M. Levitz, and, L. Romani. 2004a. The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J. Immunol. 172: 3059– 3069.

9. Bellocchio, S.,, S. Moretti,, K. Perruccio,, F. Fallarino,, S. Bozza,, C. Montagnoli,, P. Mosci,, G. B. Lipford,, L. Pitzurra, and, L. Romani. 2004b. TLRs govern neutrophil activity in aspergillosis. J. Immunol. 173: 7406– 7415.

10. Berkova, N.,, S. Lair-Fulleringer,, F. Féménia,, D. Huet,, M. C. Wagner,, K. Gorna,, F. Tournier,, O. Ibrahim-Granet,, J. Guillot,, R. Chermette,, P. Boireau, and, J. P. Latgé. 2006. Aspergillus fumigatus conidia inhibit tumour necrosis factor- or staurosporine-induced apoptosis in epithelial cells. Int. Immunol. 18: 139– 150.

11. Bernard, M., and, J. P. Latgé. 2001. Aspergillus fumigatus cell wall: composition and biosynthesis. Med. Mycol. 39(Suppl. 1): 9– 17.

12. Bodey, G. P., and, S. Vartivarian. 1989. Aspergillosis. Eur. J. Clin. Microbiol. Infect. Dis. 8: 413– 437.

13. Bonnett, C. R.,, E. J. Cornish,, A. G. Harmsen, and, J. B. Burritt. 2006. Early neutrophil recruitment and aggregation in the murine lung inhibit germination of Aspergillus fumigatus conidia. Infect. Immun. 74: 6528– 6539.

14. Boot, R. G.,, G. H. Renkema,, A. Strijland,, A. J. van Zonneveld, and, J. M. Aerts. 1995. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J. Biol. Chem. 270: 26252– 26256.

15. Borger, P.,, G. H. Koëter,, J. A. Timmerman,, E. Vellenga,, J. F. Tomee, and, H. F. Kauffman. 1999. Proteases from Aspergillus fumigatus induce interleukin (IL)-6 and IL-8 production in airway epithelial cell lines by transcriptional mechanisms. J. Infect. Dis. 180: 1267– 1274.

16. Brinkmann, V.,, U. Reichard,, C. Goosmann,, B. Fauler,, Y. Uhlemann,, D. S. Weiss,, Y. Weinrauch, and, A. Zychlinsky. 2004. Neutrophil extracellular traps kill bacteria. Science 303: 1532– 1535.

17. Brinkmann, V., and, A. Zychlinsky. 2007. Beneficial suicide: why neutrophils die to make NETs. Nat. Rev. Microbiol. 5: 577– 582.

18. Burg, N. D., and, M. H. Pillinger. 2001. The neutrophil: function and regulation in innate and humoral immunity. Clin. Immunol. 99: 7– 17.

19. Chignard, M.,, V. Balloy,, J. M. Sallenave, and, M. Si-Tahar. 2007. Role of Toll-like receptors in lung innate defense against invasive aspergillosis. Distinct impact in immunocompetent and immuno-compromized hosts. Clin. Immunol. 124: 238– 243.

20. Christin, L.,, D. R. Wysong,, T. Meshulam,, R. Hastey,, E. R. Simons, and, R. D. Diamond. 1998. Human platelets damage Aspergillus fumigatus hyphae and may supplement killing by neutrophils. Infect. Immun. 66: 1181– 1189.

21. Comera, C.,, K. Andre,, J. Laffitte,, X. Collet,, P. Galtier, and, I. Maridonneau-Parini. 2007. Gliotoxin from Aspergillus fumigatus affects phagocytosis and the organization of the actin cytoskeleton by distinct signalling pathways in human neutrophils. Microbes Infect. 9: 47– 54.

22. Cortez, K. J.,, C. A. Lyman,, S. Kottilil,, H. S. Kim,, E. Roilides,, J. Yang,, B. Fullmer,, R. Lempicki, and, T. J. Walsh. 2006. Functional genomics of innate host defense molecules in normal human monocytes in response to Aspergillus fumigatus. Infect. Immun. 74: 2353– 2365.

23. Cramer, R. A., Jr.,, M. P. Gamcsik,, R. M. Brooking,, L. K. Najvar,, W. R. Kirkpatrick,, T. F. Patterson,, C. J. Balibar,, J. R. Graybill,, J. R. Perfect,, S. N. Abraham, and, W. J. Steinbach. 2006. Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production. Eukaryot. Cell 5: 972– 980.

24. Dandona, P.,, P. Mohanty,, W. Hamouda,, A. Aljada,, Y. Kumbkarni, and, R. Garg. 1999. Effect of dexamethasone on reactive oxygen species generation by leukocytes and plasma interleukin-10 concentrations: a pharmacodynamic study. Clin. Pharmacol. Ther. 66: 58– 65.

25. De Lucca, A. J.,, J. M. Bland,, T. J. Jacks,, C. Grimm, and, T. J. Walsh. 1998. Fungicidal and binding properties of the natural peptides cecropin B and dermaseptin. Med. Mycol. 36: 291– 298.

26. Diamond, R. D.,, R. Krzesicki,, B. Epstein, and, W. Jao. 1978. Damage to hyphal forms of fungi by human leukocytes in vitro. A possible host defense mechanism in aspergillosis and mucormycosis. Am. J. Pathol. 91: 313– 328.

27. Diamond, G.,, D. Legarda, and, L. K. Ryan. 2000. The innate immune response of the respiratory epithelium. Immunol. Rev. 173: 27– 38.

28. Diniz, S. N.,, R. Nomizo,, P. S. Cisalpino,, M. M. Teixeira,, G. D. Brown,, A. Mantovani,, S. Gordon,, L. F. Reis, and, A. A. Dias. 2004. PTX3 function as an opsonin for the dectin-1-dependent internalization of zymosan by macrophages. J. Leukoc. Biol. 75: 649– 656.

29. Dubourdeau, M.,, R. Athman,, V. Balloy,, M. Huerre,, M. Chignard,, D. J. Philpott,, J. P. Latgé, and, O. Ibrahim-Granet. 2006. Aspergillus fumigatus induces innate immune responses in alveolar macrophages through the MAPK pathway independently of TLR2 and TLR4. J. Immunol. 177: 3994– 4001.

30. El-Benna, J.,, P. M. Dang,, M. A. Gougerot-Pocidalo, and, C. Elbim. 2005. Phagocyte NADPH oxidase: a multicomponent enzyme essential for host defenses. Arch. Immunol. Ther. Exp. 53: 199– 206.

31. Feldmesser, M. 2006. Role of neutrophils in invasive aspergillosis. Infect. Immun. 74: 6514– 6516.

32. Filler, S. G., and, D. C. Sheppard. 2006. Fungal invasion of normally non-phagocytic host cells. PLoS Pathog. 2: e129.

33. Fuchs, T. A.,, U. Abed,, C. Goosmann,, R. Hurwitz,, I. Schulze,, V. Wahn,, Y. Weinrauch,, V. Brinkmann, and, A. Zychlinsky. 2007. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 176: 231– 241.

34. Gallin, J. I.,, E. S. Buescher,, B. E. Seligmann,, J. Nath,, T. Gaither, and, P. Katz. 1983. NIH conference. Recent advances in chronic granulomatous disease. Ann. Intern. Med. 99: 657– 674.

35. Garlanda, C.,, E. Hirsch,, S. Bozza,, A. Salustri,, M. De Acetis,, R. Nota,, A. Maccagno,, F. Riva,, B. Bottazzi,, G. Peri,, A. Doni,, L. Vago,, M. Botto,, R. De Santis,, P. Carminati,, G. Siracusa,, F. Altruda,, A. Vecchi,, L. Romani, and, A. Mantovani. 2002. Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature 420: 182– 186.

36. Gernez-Rieux, C.,, C. Voisin,, C. Aerts,, F. Wattel, and, B. Gosselin. 1967. Experimental aspergillosis in the guinea pig. Dynamic study of the role of alveolar macrophages in the defense of the respiratory tract, after massive inhalation of Aspergillus fumigatus spores. Rev. Tuberc. Pneumol. (Paris) 31: 705– 725. (In French.)

37. Gerson, S. L.,, G. H. Talbot,, S. Hurwitz,, B. L. Strom,, E. J. Lusk, and, P. A. Cassileth. 1984. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann. Intern. Med. 100: 345– 351.

38. Gersuk, G. M.,, D. M. Underhill,, L. Zhu, and, K. A. Marr. 2006. Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states. J. Immunol. 176: 3717– 3724.

39. Gordon, S. 2002. Pattern recognition receptors: doubling up for the innate immune response. Cell 111: 927– 930.

40. Greenberg, S., and, S. Grinstein. 2002. Phagocytosis and innate immunity. Curr. Opin. Immunol. 14: 136– 145.

41. Gross, O.,, A. Gewies,, K. Finger,, M. Schafer,, T. Sparwasser,, C. Peschel,, I. Forster, and, J. Ruland. 2006. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442: 651– 656.

42. Hampton, M. B.,, A. J. Kettle, and, C. C. Winterbourn. 1998. Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood 92: 3007– 3017.

43. Hayashi, F.,, T. K. Means, and, A. D. Luster. 2003. Toll-like receptors stimulate human neutrophil function. Blood 102: 2660– 2669.

44. Hiemstra, P. S. 2002. Novel roles of protease inhibitors in infection and inflammation. Biochem. Soc. Trans. 30: 116– 120.

45. Hohl, T. M.,, H. L. Van Epps,, A. Rivera,, L. A. Morgan,, P. L. Chen,, M. Feldmesser, and, E. G. Pamer. 2005. Aspergillus fumigatus triggers inflammatory responses by stage-specific beta-glucan display. PLoS Pathog. 1: e30.

46. Ibrahim-Granet, O.,, B. Philippe,, H. Boleti,, E. Boisvieux-Ulrich,, D. Grenet,, M. Stern, and, J. P. Latgé. 2003. Phagocytosis and intracellular fate of Aspergillus fumigatus conidia in alveolar macrophages. Infect. Immun. 71: 891– 903.

47. Jaillon, S.,, G. Peri,, Y. Delneste,, I. Fremaux,, A. Doni,, F. Moalli,, C. Garlanda,, L. Romani,, H. Gascan,, S. Bellocchio,, S. Bozza,, M. A. Cassatella,, P. Jeannin, and, A. Mantovani. 2007. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J. Exp. Med. 204: 793– 804.

48. Jenssen, H.,, P. Hamill, and, R. E. Hancock. 2006. Peptide antimicrobial agents. Clin. Microbiol. Rev. 19: 491– 511.

49. Kaur, S.,, V. K. Gupta,, S. Thiel,, P. U. Sarma, and, T. Madan. 2007. Protective role of mannan-binding lectin in a murine model of invasive pulmonary aspergillosis. Clin. Exp. Immunol. 148: 382– 389.

50. Kim, J. Y.,, S. Y. Lee,, S. C. Park,, S. Y. Shin,, S. J. Choi,, Y. Park, and, K. S. Hahm. 2007. Purification and antimicrobial activity studies of the N-terminal fragment of ubiquitin from human amniotic fluid. Biochim. Biophys. Acta 1774: 1221– 1226.

51. Kobayashi, S. D.,, J. M. Voyich,, C. Burlak, and, F. R. DeLeo. 2005. Neutrophils in the innate immune response. Arch. Immunol. Ther. Exp. 53: 505– 517.

52. Kogan, T. V.,, J. Jadoun,, L. Mittelman,, K. Hirschberg, and, N. Osherov. 2004. Involvement of secreted Aspergillus fumigatus proteases in disruption of the actin fiber cytoskeleton and loss of focal adhesion sites in infected A549 lung pneumocytes. J. Infect. Dis. 189: 1965– 1973.

53. Korkmaz, B.,, T. Moreau, and, F. Gauthier. 2008. Neutrophil elastase, proteinase 3 and cathepsin G: physicochemical properties, activity and physiopathological functions. Biochimie 90: 227– 242.

54. Kupfahl, C.,, T. Heinekamp,, G. Geginat,, T. Ruppert,, A. Hartl,, H. Hof, and, A. A. Brakhage. 2006. Deletion of the gliP gene of Aspergillus fumigatus results in loss of gliotoxin production but has no effect on virulence of the fungus in a low-dose mouse infection model. Mol. Microbiol. 62: 292– 302.

55. Latgé, J. P. 2001. The pathobiology of Aspergillus fumigatus. Trends Microbiol. 9: 382– 389.

56. Laube, D. M.,, S. Yim,, L. K. Ryan,, K. O. Kisich, and, G. Diamond. 2006. Antimicrobial peptides in the airway. Curr. Top. Microbiol. Immunol. 306: 153– 182.

57. Lee, Y. T.,, D. H. Kim,, J. Y. Suh,, J. H. Chung,, B. L. Lee,, Y. Lee, and, B. S. Choi. 1999. Structural characteristics of tenecin 3, an insect antifungal protein. Biochem. Mol. Biol. Int. 47: 369– 376.

58. Lehrer, R. I. 2007. Multispecific myeloid defensins. Curr. Opin. Hematol. 14: 16– 21.

59. Lehrer, R. I., and, R. G. Jan. 1970. Interaction of Aspergillus fumigatus spores with human leukocytes and serum. Infect. Immun. 1: 345– 350.

60. Levitz, S. M., and, R. D. Diamond. 1985. Mechanisms of resistance of Aspergillus fumigatus conidia to killing by neutrophils in vitro. J. Infect. Dis. 152: 33– 42.

61. Levitz, S. M.,, M. E. Selsted,, T. Ganz,, R. I. Lehrer, and, R. D. Diamond. 1986. In vitro killing of spores and hyphae of Aspergillus fumigatus and Rhizopus oryzae by rabbit neutrophil cationic peptides and bronchoalveolar macrophages. J. Infect. Dis. 154: 483– 489.

62. Luther, K., and, K. Ebel. 2006. Toll-like receptors: recent advances, open questions and implications for aspergillosis control. Med. Mycol. 44: S219– S227.

63. Luther, K.,, A. Torosantucci,, A. A. Brakhage,, J. Heesemann, and, F. Ebel. 2007. Phagocytosis of Aspergillus fumigatus conidia by murine macrophages involves recognition by the dectin-1 beta-glucan receptor and Toll-like receptor 2. Cell. Microbiol. 9: 368– 381.

64. Madan, T.,, P. Eggleton,, U. Kishore,, P. Strong,, S. S. Aggrawal,, P. U. Sarma, and, K. B. Reid. 1997. Binding of pulmonary surfactant proteins A and D to Aspergillus fumigatus conidia enhances phagocytosis and killing by human neutrophils and alveolar macrophages. Infect. Immun. 65: 3171– 3179.

65. Madan, T.,, S. Kaur,, S. Saxena,, M. Singh,, U. Kishore,, S. Thiel,, K. B. Reid, and, P. U. Sarma. 2005. Role of collectins in innate immunity against aspergillosis. Med. Mycol. 43(Suppl. l): S155– S163.

66. Mambula, S. S.,, K. Sau,, P. Henneke,, D. T. Golenbock, and, S. M. Levitz. 2002. Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus. J. Biol. Chem. 277: 39320– 39326.

67. Mamishi, S.,, N. Parvaneh,, A. Salavati,, S. Abdollahzadeh, and, M. Yeganeh. 2007. Invasive aspergillosis in chronic granulomatous disease: report of 7 cases. Eur. J. Pediatr. 166: 83– 84.

68. Martinon, F.,, O. Gaide,, V. Pétrilli,, A. Mayor, and, J. Tschopp. 2007. NALP inflammasomes: a central role in innate immunity. Semin. Immunopathol. 29: 213– 229.

69. Medzhitov, R. 2007. Recognition of microorganisms and activation of the immune response. Nature 449: 819– 826.

70. Medzhitov, R. and, C. A. Janeway, Jr. 1997. Innate immunity: impact on the adaptive immune response. Curr. Opin. Immunol. 9: 4– 9.

71. Medzhitov, R., and, C. Janeway, Jr. 2000. Innate immunity. N. Engl. J. Med. 343: 338– 344.

72. Meier, A.,, C. J. Kirschning,, T. Nikolaus,, H. Wagner,, J. Heesemann, and, F. Ebel. 2003. Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages. Cell. Microbiol. 5: 561– 570.

73. Message, S. D., and, S. L. Johnston. 2004. Host defense function of the airway epithelium in health and disease: clinical background. J. Leukoc. Biol. 75: 5– 17.

74. Michaliszyn, E.,, S. Senechal,, P. Martel, and, L. de Repentigny. 1995. Lack of involvement of nitric oxide in killing of AsperiMoraesgllus fumigatus conidia by pulmonary alveolar macrophages. Infect. Immun. 63: 2075– 2078.

75. Moraes, T. J.,, J. H. Zurawska, and, G. P. Downey. 2006. Neutrophil granule contents in the pathogenesis of lung injury. Curr. Opin. Hematol. 13: 21– 27.

76. Morgenstern, D. E.,, V. Gifford,, M. A. Li,, C. M. Doerschuk, and, M. C. Dinauer. 1997. Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus. J. Exp. Med. 185: 207– 218.

77. Mullbacher, A.,, P. Waring, and, R. D. Eichner. 1985. Identification of an agent in cultures of Aspergillus fumigatus displaying anti-phagocytic and immunomodulating activity in vitro. J. Gen. Microbiol. 131: 1251– 1258.

78. Nathan, C. 2006. Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol. 6: 173– 182.

79. Netea, M. G.,, G. Ferwerda,, C. A. van der Graaf,, J. W. Van der Meer, and, B. J. Kullberg. 2006. Recognition of fungal pathogens by tolllike receptors. Curr. Pharm. Des. 12: 4195– 4201.

80. Netea, M. G.,, A. Warris,, J. W. Van der Meer,, M. J. Fenton,, T. J. Verver-Janssen,, L. E. Jacobs,, T. Andresen,, P. E. Verweij, and, B. J. Kullberg. 2003. Aspergillus fumigatus evades immune recognition during germination through loss of toll-like receptor-4-mediated signal transduction. J. Infect. Dis. 188: 320– 326.

81. Olenchock, S. A.,, M. S. Mentnech,, J. C. Mull,, M. E. Gladish,, F. H. Green, and, P. C. Manor. 1979. Complement, polymorphonuclear leukocytes and platelets in acute experimental respiratory reactions to Aspergillus. Comp. Immunol. Microbiol. Infect. Dis. 2: 113– 124.

82. Orciuolo, E.,, M. Stanzani,, M. Canestraro,, S. Galimberti,, G. Carulli,, R. Lewis,, M. Petrini, and, K. V. Komanduri. 2007. Effects of Aspergillus fumigatus gliotoxin and methylprednisolone on human neutrophils: implications for the pathogenesis of invasive aspergillosis. J. Leukoc. Biol. 82: 839– 848.

83. Paris, S.,, E. Boisvieux-Ulrich,, B. Crestani,, O. Houcine,, D. Taramelli,, L. Lombardi, and, J. P. Latgé. 1997. Internalization of Aspergillus fumigatus conidia by epithelial and endothelial cells. Infect. Immun. 65: 1510– 1514.

84. Pham, C. T. 2006. Neutrophil serine proteases: specific regulators of inflammation. Nat. Rev. Immunol. 6: 541– 550.

85. Philippe, B.,, O. Ibrahim-Granet,, M. C. Prevost,, M. A. Gougerot-Pocidalo,, M. Sanchez Perez,, A. Van der Meeren, and, J. P. Latgé. 2003. Killing of Aspergillus fumigatus by alveolar macrophages is mediated by reactive oxidant intermediates. Infect. Immun. 71: 3034– 3042.

86. Robinson, B. W.,, T. J. Venaille,, A. H. Mendis, and, R. McAleer. 1990. Allergens as proteases: an Aspergillus fumigatus proteinase directly induces human epithelial cell detachment. J. Allergy Clin. Immunol. 86: 726– 731.

87. Rodriguez, E.,, F. Boudard,, M. Mallie,, J. M. Bastide, and, M. Bastide. 1997. Murine macrophage elastolytic activity induced by Aspergillus fumigatus strains in vitro: evidence of the expression of two macrophage-induced protease genes. Can. J. Microbiol. 43: 649– 657.

88. Romani, L. 2004. Immunity to fungal infections. Nat. Rev. Immunol. 4: 1– 23.

89. Roos, D.,, R. van Bruggen, and, C. Meischl. 2003. Oxidative killing of microbes by neutrophils. Microbes Infect. 5: 1307– 1315.

90. Russo-Marie, F. 1992. Macrophages and the glucocorticoids. J. Neuroimmunol. 40: 281– 286.

91. Schaffner, A.,, H. Douglas, and, A. Braude. 1982. Selective protection against conidia by mononuclear and against mycelia by polymor-phonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J. Clin. Investig. 69: 617– 631.

92. Segal, A. W. 2005. How neutrophils kill microbes. Annu. Rev. Immunol. 23: 197– 223.

93. Segal, B. H., and, T. J. Walsh. 2006. Current approaches to diagnosis and treatment of invasive aspergillosis. Am. J. Respir. Crit. Care Med. 173: 707– 717.

94. Semple, C. A.,, P. Gautier,, K. Taylor, and, J. R. Dorin. 2006. The changing of the guard: molecular diversity and rapid evolution of beta-defensins. Mol. Divers. 10: 575– 584.

95. Serrano-Gomez, D.,, A. Dominguez-Soto,, J. Ancochea,, J. A. Jimenez-Heffernan,, J. A. Leal, and, A. L. Corbi. 2004. Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin mediates binding and internalization of Aspergillus fumigatus conidia by dendritic cells and macrophages. J. Immunol. 173: 5635– 5643.

96. Shepherd, V. L. 1986. The role of the respiratory burst of phagocytes in host defense. Semin. Respir. Infect. 1: 99– 106.

97. Sibille, Y., and, H. Y. Reynolds. 1990. Macrophages and polymorphonuclear neutrophils in lung defense and injury. Am. Rev. Respir. Dis. 141: 471– 501.

98. Smith, J. A. 1994. Neutrophils, host defense, and inflammation: a double-edged sword. J. Leukoc. Biol. 56: 672– 686.

99. Smith, P. D,, C. Ochsenbauer-Jambor, and, L. E. Smythies. 2005. Intestinal macrophages: unique effector cells of the innate immune system. Immunol. Rev. 206: 149– 159.

100. Spikes, S.,, R. Xu,, C. K. Nguyen,, G. Chamilos,, D. P. Kontoyiannis,, R. H. Jacobson,, D. E. Ejzykowicz,, L. Y. Chiang,, S. G. Filler, and, G. S. May. 2008. Gliotoxin production in Aspergillus fumigatus contributes to host-specific differences in virulence. J. Infect. Dis. 197: 479– 486.

101. Steele, C.,, R. R. Rapaka,, A. Metz,, S. M. Pop,, D. L. Williams,, S. Gordon,, J. K. Kolls, and, G. D. Brown. 2005. The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. PLoS Pathog. 1: e42.

102. Stephens-Romero, S. D.,, A. J. Mednick, and, M. Feldmesser. 2005. The pathogenesis of fatal outcome in murine pulmonary aspergillosis depends on the neutrophil depletion strategy. Infect. Immun. 73: 114– 125.

103. Stergiopoulou, T.,, J. Meletiadis,, E. Roilides,, D. E. Kleiner,, R. Schaufele,, M. Roden,, S. Harrington,, L. Dad,, B. Segal, and, T. J. Walsh. 2007. Host-dependent patterns of tissue injury in invasive pulmonary aspergillosis. Am. J. Clin. Pathol. 127: 349– 355.

104. Strieter, R. M.,, J. A. Belperio, and, M. P. Keane. 2002. Cytokines in innate host defense in the lung. J. Clin. Investig. 109: 699– 705.

105. Stuart, L. M., and, R. A. Ezekowitz. 2005. Phagocytosis: elegant complexity. Immunity 22: 539– 550.

106. Sturtevant, J., and, J. P. Latgé. 1992. Participation of complement in the phagocytosis of the conidia of Aspergillus fumigatus by human polymorphonuclear cells. J. Infect. Dis. 166: 580– 586.

107. Sugui, J. A.,, J. Pardo,, Y. C. Chang,, K. A. Zarember,, G. Nardone,, E. M. Galvez,, A. Mullbacher,, J. I. Gallin,, M. M. Simon, and, K. J. Kwon-Chung. 2007. Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone. Eukaryot. Cell 6: 1562– 1569.

108. Taylor, P. R.,, G. D. Brown,, D. M. Reid,, J. A. Willment,, L. Martinez-Pomares,, S. Gordon, and, S. Y. Wong. 2002. The beta-glucan receptor, dectin-1, is predominantly expressed on the surface of cells of the monocyte/macrophage and neutrophil lineages. J. Immunol. 169: 3876– 3882.

109. Taylor, P. R.,, L. Martinez-Pomares,, M. Stacey,, H. H. Lin,, G. D. Brown, and, S. Gordon. 2005. Macrophage receptors and immune recognition. Annu. Rev. Immunol. 23: 901– 944.

110. Tkalcevic, J.,, M. Novelli,, M. Phylactides,, J. P. Iredale,, A. W. Segal, and, J. Roes. 2000. Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity 12: 201– 210.

111. Tomee, J. F.,, P. S. Hiemstra,, R. Heinzel-Wieland, and, H. F. Kauffman. 1997. Antileukoprotease: an endogenous protein in the innate mucosal defense against fungi. J. Infect. Dis. 176: 740– 747.

112. Tomee, J. F.,, A. T. Wierenga,, P. S. Hiemstra, and, H. K. Kauffman. 1997. Proteases from Aspergillus fumigatus induce release of proin-flammatory cytokines and cell detachment in airway epithelial cell lines. J. Infect. Dis. 176: 300– 303.

113. Tsunawaki, S.,, L. S. Yoshida,, S. Nishida,, T. Kobayashi, and, T. Shimoyama. 2004. Fungal metabolite gliotoxin inhibits assembly of the human respiratory burst NADPH oxidase. Infect. Immun. 72: 3373– 3382.

114. Umeki, S. 1994. Mechanisms for the activation/electron transfer of neutrophil NADPH-oxidase complex and molecular pathology of chronic granulomatous disease. Ann. Hematol. 68: 267– 277.

115. Underhill, D. M. 2007. Collaboration between the innate immune receptors dectin-1, TLRs, and NODs. Immunol. Rev. 219: 75– 87.

116. Urban, C. F.,, U. Reichard,, V. Brinkmann, and, A. Zychlinsky. 2006. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell. Microbiol. 8: 668– 676.

117. Waldorf, A. R.,, S. M. Levitz, and, R. D. Diamond. 1984. In vivo bronchoalveolar macrophage defense against Rhizopus oryzae and Aspergillus fumigatus. J. Infect. Dis. 150: 752– 760.

118. Walsh, T. J., and, D. M. Dixon. 1989. Nosocomial aspergillosis: environmental microbiology, hospital epidemiology, diagnosis and treatment. Eur. J. Epidemiol. 5: 131– 142.

119. Wasylnka, J. A., and, M. M. Moore. 2002. Uptake of Aspergillus fumigatus conidia by phagocytic and nonphagocytic cells in vitro: quantitation using strains expressing green fluorescent protein. Infect. Immun. 70: 3156– 3163.

120. Wasylnka, J. A., and, M. M. Moore. 2003. Aspergillus fumigatus conidia survive and germinate in acidic organelles of A549 epithelial cells. J. Cell Sci. 116: 1579– 1587.

121. Weinberger, M.,, I. Elattar,, D. Marshall,, S. M. Steinberg,, R. L. Redner,, N. S. Young, and, P. Pizzo. 1992. Patterns of infection in patients with aplastic anemia and the emergence of Aspergillus as a major cause of death. Medicine 71: 24– 43.

122. Weiss, S. J. 1989. Tissue destruction by neutrophils. N. Engl. J. Med. 320: 365– 376.

123. Werts, C.,, S. E. Girardin, and, D. J. Philpott. 2006. TIR, CARD and PYRIN: three domains for an antimicrobial triad. Cell Death Differ. 13: 798– 815.

124. Wiedow, O., and, U. Meyer-Hoffert. 2005. Neutrophil serine proteases: potential key regulators of cell signalling during inflammation. J. Intern. Med. 257: 319– 328.

125. Wiley, J. M.,, N. Smith,, B. G. Leventhal,, M. L. Graham,, L. C. Strauss,, C. A. Hurwitz,, J. Modlin,, D. Mellits,, R. Baumgardner,, B. J. Corden, and, C. I. Civin. 1990. Invasive fungal disease in pediatric acute leukemia patients with fever and neutropenia during induction chemotherapy: a multivariate analysis of risk factors. J. Clin. Oncol. 8: 280– 286.

126. Witko-Sarsat, V.,, P. Rieu,, B. Descamps-Latscha,, P. Lesavre, and, L. Halbwachs-Mecarelli. 2000. Neutrophils: molecules, functions and pathophysiological aspects. Lab. Investig. 80: 617– 653.

127. Zarember, K. A.,, J. A. Sugui,, Y. C. Chang,, K. J. Kwon-Chung, and, J. I. Gallin. 2007. Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion. J. Immunol. 178: 6367– 6373.

128. Zelante, T.,, C. Montagnoli,, S. Bozza,, R. Gaziano,, S. Bellocchio,, P. Bonifazi,, S. Moretti,, F. Fallarino,, P. Puccetti, and, L. Romani. 2007. Receptors and pathways in innate antifungal immunity: the implication for tolerance and immunity to fungi. Adv. Exp. Med. Biol. 590: 209– 221.

129. Zhang, Z.,, R. Liu,, J. A. Noordhoek, and, H. F. Kauffman. 2005. Interaction of airway epithelial cells (A549) with spores and mycelium of Aspergillus fumigatus. J. Infect. 51: 375– 382.