Chapter 37 : Fungal Interactions with Leukocytes

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This chapter discusses host defenses in the lungs and the role played by fungal virulence factors in allowing the organism to survive inside the host and either cause disease or remain latent.. On inhalation from the environment, fungi first encounter the barrier defenses of the lungs (cough reflexes, airway secretions, and mucociliary action of the upper airway epithelium). Alveolar macrophages, dendritic cells (DC), and recruited neutrophils and monocytes compose the phagocytic cells of the pulmonary innate immune system. Secretion of TNF-α by innate immune cells is critical for the development of protective adaptive immunity. IFN- γ production is critical for clearance of fungal infections in the lungs by activating macrophages and other phagocytes to ingest and kill fungi. Taken together, these observations demonstrate the importance of Th1-cell production of IFN-γ in pulmonary host defense against fungi. Susceptibility against pulmonary fungal infections in otherwise healthy individuals is associated with the production of Th2 cytokines such as IL-4, IL-5, and IL-10. The maturation state or phenotype of DC is perhaps the most important regulatory step in the development of T-cell immunity in the lungs. Many of these moieties can stimulate inflammatory cytokine production by lung leukocytes when administered in pure form. Although B cells are discussed last in the list of cells that interact with fungi, their role in modulating host defense against fungi cannot be understated. The majority of human fungal pathogens are opportunistic ubiquitous organisms, causing disease only under permissive conditions.

Citation: Noverr M, Lindell D, Toews G, Huffnagle G. 2006. Fungal Interactions with Leukocytes, p 555-563. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch37
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Figure 1

Model for how the gut microbiota might regulate pulmonary immune responses. Antigen (Ag) initially comes in contact with the lung during infection (microbe + Ag) or inhalation (Ag). This antigen is captured by cells of the innate immune system, which then stimulate adaptive immune responses in secondary lymphoid organs such as the lymph nodes or spleen. Antigen-specific T cells are recruited to the lungs on subsequent antigen exposure. To prevent the development of allergic inflammatory (Th2) responses to inhaled antigens that are noninfectious (pollens) or of extremely low infectivity (mold spores), regulatory T-cell networks produce anti-inflammatory mediators that down-regulate inflammatory T-cell activities. Inhaled antigens are also swallowed because the anatomy of the sinuses and upper airways is designed to trap environmental antigens (aerosols, microparticulates, and macroparticulates) in the mucus layer and then “sweep” them into the throat, where they are swallowed. Swallowed Ags are then acquired by DC in the gut. Under noninflammatory conditions, these DC promote the development of a regulatory T-cell response to the Ag, which can control reexposure responses in the lungs in the absence of infection. The precise mechanism by which the gastrointestinal microbiota balance helps to maintain the T-cell regulatory networks that mediate oral tolerance is unknown.

Citation: Noverr M, Lindell D, Toews G, Huffnagle G. 2006. Fungal Interactions with Leukocytes, p 555-563. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch37
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1. Allendoerfer, R., and, G. S. Deepe, Jr. 1998 Blockade of endogenous TNF-α exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms. J. Immunol. 160: 60726082.
2. Allendoerfer, R., and, G. S. Deepe,, Jr. 1997 Intrapulmonary response to Histoplasma capsulatum in gamma interferon knockout mice. Infect. Immun. 65: 25642569.
3. Allendoerfer, R., and, G. S. Deepe, Jr. 2000 Regulation of infection with Histoplasma capsulatum by TNFR1 and -2. J. Immunol. 165: 26572664.
4. Allendorfer, R., G., D. Brunner, and, G. S. Deepe, Jr. 1999 Complex requirements for nascent and memory immunity in pulmonary histoplasmosis. J. Immunol. 162: 73897396.
5. Arruda, C.,, R. C. Valente-Ferreira,, A. Pina,, S. S. Kashino,, R. A. Fazioli,, C. A. Vaz,, M. F. Franco,, A. C. Keller, and, V. L. Calich. 2004 Dual role of interleukin-4 (IL-4) in pulmonary paracoccidioidomycosis: endogenous IL-4 can induce protection or exacerbation of disease depending on the host genetic pattern. Infect. Immun. 72: 39323940.
6. Bauman, S. K.,, G. B. Huffnagle, and, J. W. Murphy. 2003 Effects of tumor necrosis factor alpha on dendritic cell accumulation in lymph nodes draining the immunization site and the impact on the anticryptococcal cell-mediated immune response. Infect. Immun. 71: 6874.
7. Beck, J. M.,, R. L. Newbury,, B. E. Palmer,, M. L. Warnock,, P. K. Byrd, and, H. B. Kaltreider. 1996 Role of CD8 + lymphocytes in host defense against Pneumocystis carinii in mice. J. Lab. Clin. Med. 128: 477487.
8. Bozza, S.,, R. Gaziano,, A. Spreca,, A. Bacci,, C. Montagnoli,, P. di Francesco,and, L. Romani. 2002 Dendritic cells transport conidia and hyphae of Aspergillus fumigatus from the airways to the draining lymph nodes and initiate disparate Th responses to the fungus. J. Immunol. 168: 13621371.
9. Brieland, J. K.,, C. Jackson,, F. Menzel,, D. Loebenberg,, A. Cacciapuoti,, J. Halpern,, S. Hurst,, T. Muchamuel,, R. Debets,, R. Kastelein,, T. Churakova,, J. Abrams,, R. Hare,and, A. O’Garra. 2001 Cytokine networking in lungs of immunocompetent mice in response to inhaled Aspergillus fumigatus. Infect. Immun. 69: 15541560.
10. Cano, L. E.,, L. M. Singer-Vermes,, T. A. Costa,, J. O. Mengel,, C. F. Xidieh,, C. Arruda,, D. C. Andre,, C. A. Vaz,, E. Burger,and, V. L. Calich. 2000 Depletion of CD8 + T cells in vivo impairs host defense of mice resistant and susceptible to pulmonary paracoccidioidomycosis. Infect. Immun. 68: 352359.
11. Cenci, E.,, A. Mencacci,, G. Del Sero,, A. Bacci,, C. Montagnoli,, C. F. d’Ostiani,, P. Mosci,, M. Bachmann,, F. Bistoni,, M. Kopf,and, L. Romani. 1999 Interleukin-4 causes susceptibility to invasive pulmonary aspergillosis through suppression of protective type I responses. J. Infect. Dis. 180: 19571968.
12. Chaturvedi, V.,, B. Wong,and, S. L. Newman. 1996 Oxidative killing of Cryptococcus neoformans by human neutrophils. Evidence that fungal mannitol protects by scavenging reactive oxygen intermediates. J. Immunol. 156: 38363840.
13. Chen, W.,, E. A. Havell,and, A. G. Harmsen. 1992 Importance of endogenous tumor necrosis factor alpha and gamma interferon in host resistance against Pneumocystis carinii infection. Infect. Immun. 60: 12791284.
14. Cox, R. A., and, D. M. Magee. 1995 Production of tumor necrosis factor alpha, interleukin-1 alpha, and interleukin-6 during murine coccidioidomycosis. Infect. Immun. 63: 41784180.
15. Deepe, G. S.,, Jr. 2000 Immune response to early and late Histoplasma capsulatum infections. Curr. Opin. Microbiol. 3: 359362.
16. Diamond, R. D. 1993 Invasive aspergillosis: host defenses. Recent Results Cancer Res. 132: 109115.
17. d’Ostiani, C. F.,, G. Del Sero,, A. Bacci,, C. Montagnoli,, A. Spreca,, A. Mencacci,, P. Ricciardi-Castagnoli, and, L. Romani. 2000 Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. Implications for initiation of T helper cell immunity in vitro and in vivo. J. Exp. Med. 191: 16611674.
18. Ellerbroek, P. M.,, A. M. Walenkamp,, A. I. Hoepelman,and, F. E. Coenjaerts. 2004 Effects of the capsular polysaccharides of Cryptococcus neoformans on phagocyte migration and inflammatory mediators. Curr. Med. Chem. 11: 253266.
19. Fang, F. C. 2004 Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat. Rev. Microbiol. 2: 820832.
20. Fels, A. O., and, Z. A. Cohn. 1986 The alveolar macrophage. J. Appl. Physiol. 60: 353369.
21. Finkel-Jimenez, B.,, M. Wuthrich,, T. Brandhorst, and, B. S. Klein. 2001 The WI-1 adhesin blocks phagocyte TNF-α production, imparting pathogenicity on Blastomyces dermatitidis. J. Immunol. 166: 26652673.
22. Forster, R.,, A. Schubel,, D. Breitfeld,, E. Kremmer,, I. Renner-Muller,, E. Wolf, and, M. Lipp. 1999 CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99: 2333.
23. 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: 182186.
24. Gildea, L. A.,, R. E. Morris, and, S. L. Newman. 2001 Histoplasma capsulatum yeasts are phagocytosed via very late antigen-5, killed, and processed for antigen presentation by human dendritic cells. J. Immunol. 166: 10491056.
25. Grutz, G. 2005 New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J. Leukoc. Biol. 77: 315.
26. Herring, A. C.,, J. Lee,, R. A. McDonald,, G. B. Toews, and, G. B. Huffnagle. 2002 Induction of interleukin-12 and gamma interferon requires tumor necrosis factor alpha for protective T1-cell-mediated immunity to pulmonary Cryptococcus neoformans infection. Infect. Immun. 70: 29592964.
27. Hogaboam, C. M.,, K. Blease, and, J. M. Schuh. 2003 Cytokines and chemokines in allergic bronchopulmonary aspergillosis (ABPA) and experimental Aspergillus- induced allergic airway or asthmatic disease. Front. Biosci. 8: e147e156.
28. Hori, S.,, T. L. Carvalho, and, J. Demengeot. 2002 CD25 + CD4 + regulatory T cells suppress CD4 + T cell-mediated pulmonary hyperinflammation driven by Pneumocystis carinii in immunodeficient mice. Eur. J. Immunol. 32: 12821291.
29. Hostetler, J. S.,, E. Brummer,, R. L. Coffman, and, D. A. Stevens. 1993 Effect of anti-IL-4, interferon-gamma and an antifungal triazole (SCH 42427) in paracoccidioidomycosis: correlation of IgE levels with outcome. Clin. Exp. Immunol. 94: 1116.
30. Huffnagle, G. B.,, M. B. Boyd,, N. E. Street, and, M. F. Lipscomb. 1998 IL-5 is required for eosinophil recruitment, crystal deposition, and mononuclear cell recruitment during a pulmonary Cryptococcus neoformans infection in genetically susceptible mice (C57BL/6). J. Immunol. 160: 23932400.
31. Huffnagle, G. B.,, G. B. Toews,, M. D. Burdick,, M. B. Boyd,, K. S. McAllister,, R. A. McDonald,, S. L. Kunkel, and, R. M. Strieter. 1996 Afferent phase production of TNF-α is required for the development of protective T cell immunity to Cryptococcus neoformans. J. Immunol. 157: 45294536.
32. Jonuleit, H.,, E. Schmitt,, K. Steinbrink, and, A. H. Enk. 2001 Dendritic cells as a tool to induce anergic and regulatory T cells. Trends Immunol. 22: 394400.
33. Kashino, S. S.,, R. A. Fazioli,, C. Cafalli-Favati,, L. H. Meloni-Bruneri,, C. A. Vaz,, E. Burger,, L. M. Singer, and, V. L. Calich. 2000. Resistance to Paracoccidioides brasiliensis infection is linked to a preferential Th1 immune response, whereas susceptibility is associated with absence of IFN-γ production. J. Interferon Cytokine Res. 20: 8997.
34. Kawakami, K.,, M. Hossain Qureshi,, T. Zhang,, Y. Koguchi,, Q. Xie,, M. Kurimoto, and, A. Saito. 1999 Interleukin-4 weakens host resistance to pulmonary and disseminated cryptococcal infection caused by combined treatment with interferon-gamma-inducing cytokines. Cell. Immunol. 197: 5561.
35. Kawakami, K.,, M. H. Qureshi,, Y. Koguchi,, T. Zhang,, H. Okamura,, M. Kurimoto, and, A. Saito. 1999. Role of TNF-α in the induction of fungicidal activity of mouse peritoneal exudate cells against Cryptococcus neoformans by IL-12 and IL-18. Cell. Immunol. 193: 916.
36. Kawakami, K.,, M. Tohyama,, X. Qifeng, and, A. Saito. 1997. Expression of cytokines and inducible nitric oxide synthase mRNA in the lungs of mice infected with Cryptococcus neoformans: effects of interleukin-12. Infect. Immun. 65: 13071312.
37. Kheradmand, F.,, A. Kiss,, J. Xu,, S. H. Lee,, P. E. Kolattukudy, and, D. B. Corry. 2002 A protease-activated pathway underlying Th cell type 2 activation and allergic lung disease. J. Immunol. 169: 59045911.
38. Latge, J. P. 2001 The pathobiology of Aspergillus fumigatus. Trends Microbiol. 9: 382389.
39. Lee, J. H.,, N. R. Slifman,, S. K. Gershon,, E. T. Edwards,, W. D. Schwieterman,, J. N. Siegel,, R. P. Wise,, S. L. Brown,, J. N. Udall, Jr., and, M. M. Braun. 2002 Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum. 46: 25652570.
40. Levitz, S. M. 2004 Interactions of Toll-like receptors with fungi. Microbes Infect. 6: 13511355.
41. Levitz, S. M., and, T. P. Farrell. 1990 Human neutrophil degranulation stimulated by Aspergillus fumigatus. J. Leukoc. Biol. 47: 170175.
42. Lindell, D. M., and, G. B. Huffnagle. 2005 Cell-mediated immunity to C. neoformans in the lungs, p. 157180. In P. L. Fidel and G. B. Huffnagle (ed.), Fungal Immunology from an Organ Perspective. Kluwer, New York, N.Y.
43. Liu, T.,, T. Matsuguchi,, N. Tsuboi,, T. Yajima, and, Y. Yoshikai. 2002 Differences in expression of Toll-like receptors and their reactivities in dendritic cells in BALB/c and C57BL/6 mice. Infect. Immun. 70: 66386645.
44. Long, K. H.,, F. J. Gomez,, R. E. Morris, and, S. L. Newman. 2003 Identification of heat shock protein 60 as the ligand on Histoplasma capsulatum that mediates binding to CD18 receptors on human macrophages. J. Immunol. 170: 487494.
45. Magee, D. M., and, R. A. Cox. 1995 Roles of gamma interferon and interleukin-4 in genetically determined resistance to Coccidioides immitis. Infect. Immun. 63: 35143519.
46. 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: 3932039326.
47. Mambula, S. S.,, E. R. Simons,, R. Hastey,, M. E. Selsted, and, S. M. Levitz. 2000 Human neutrophil-mediated nonoxidative antifungal activity against Cryptococcus neoformans. Infect. Immun. 68: 62576264.
48. Mansour, M. K., and, S. M. Levitz. 2002 Interactions of fungi with phagocytes. Curr. Opin. Microbiol. 5: 359365.
49. Mansour, M. K.,, L. S. Schlesinger, and, S. M. Levitz. 2002 Optimal T cell responses to Cryptococcus neoformans mannoprotein are dependent on recognition of conjugated carbohydrates by mannose receptors. J. Immunol. 168: 28722879.
50. McGuirk, P., and, K. H. Mills. 2002 Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases. Trends Immunol. 23: 450455.
51. Mednick, A. J.,, M. Feldmesser,, J. Rivera, and, A. Casadevall. 2003 Neutropenia alters lung cytokine production in mice and reduces their susceptibility to pulmonary cryptococcosis. Eur. J. Immunol. 33: 17441753.
52. Mencacci, A.,, E. Cenci,, G. Del Sero,, C. Fe d’Ostiani,, P. Mosci,, C. Montagnoli,, A. Bacci,, F. Bistoni,, V. F. Quesniaux,, B. Ryffel, and, L. Romani. 1998 Defective co-stimulation and impaired Th1 development in tumor necrosis factor/lymphotoxin-alpha double-deficient mice infected with Candida albicans. Int. Immunol. 10: 3748.
53. Newman, S. L. 2001 Cell-mediated immunity to Histoplasma capsulatum. Semin. Respir. Infect. 16: 102108.
54. Newman, S. L.,, L. Gootee,, J. E. Gabay, and, M. E. Selsted. 2000 Identification of constituents of human neutrophil azurophil granules that mediate fungistasis against Histoplasma capsulatum. Infect. Immun. 68: 56685672.
55. Noverr, M. C.,, J. R. Erb-Downward, and, G. B. Huffnagle. 2003 Production of eicosanoids and other oxylipins by pathogenic eukaryotic microbes. Clin. Microbiol. Rev. 16: 517533.
56. Noverr, M. C.,, N. R. Falkowski,, R. A. McDonald,, A. N. McKenzie, and, G. B. Huffnagle. 2005 Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13. Infect. Immun. 73: 3038.
57. Noverr, M. C., and, G. B. Huffnagle. 2004 Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 12: 562568.
58. Noverr, M. C.,, R. M. Noggle,, G. B. Toews, and, G. B. Huffnagle. 2004 Role of antibiotics and fungal micro-biota in driving pulmonary allergic responses. Infect. Immun. 72: 49965003.
59. Noverr, M. C.,, S. M. Phare,, G. B. Toews,, M. J. Coffey, and, G. B. Huffnagle. 2001 Pathogenic yeasts Cryptococcus neoformans and Candida albicans produce immunomodulatory prostaglandins. Infect. Immun. 69: 29572963.
60. Noverr, M. C.,, G. B. Toews, and, G. B. Huffnagle. 2002 Production of prostaglandins and leukotrienes by pathogenic fungi. Infect. Immun. 70: 400402.
61. Roilides, E.,, A. Dimitriadou,, I. Kadiltsoglou,, T. Sein,, J. Karpouzas,, P. A. Pizzo, and, T. J. Walsh. 1997 IL-10 exerts suppressive and enhancing effects on antifungal activity of mononuclear phagocytes against Aspergillus fumigatus. J. Immunol. 158: 322329.
62. Roilides, E.,, I. Kadiltsoglou,, A. Dimitriadou,, M. Hatzistilianou,, A. Manitsa,, J. Karpouzas,, P. A. Pizzo, and, T. J. Walsh. 1997 Interleukin-4 suppresses antifungal activity of human mononuclear phagocytes against Candida albicans in association with decreased uptake of blastoconidia. FEMS Immunol. Med. Microbiol. 19: 169180.
63. Saeki, H.,, A. M. Moore,, M. J. Brown, and, S. T. Hwang. 1999 Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J. Immunol. 162: 24722475.
64. Sieling, P. A., and, R. L. Modlin. 2002 Toll-like receptors: mammalian “taste receptors” for a smorgasbord of microbial invaders. Curr. Opin. Microbiol. 5: 7075.
65. Souto, J. T.,, F. Figueiredo,, A. Furlanetto,, K. Pfeffer,, M. A. Rossi, and, J. S. Silva. 2000 Interferon-gamma and tumor necrosis factor-alpha determine resistance to Paracoccidioides brasiliensis infection in mice. Am. J. Pathol. 156: 18111820.
66. Syme, R. M.,, J. C. Spurrell,, E. K. Amankwah,, F. H. Green, and, C. H. Mody. 2002 Primary dendritic cells phagocytose Cryptococcus neoformans via mannose receptors and Fcγ receptor II for presentation to T lymphocytes. Infect. Immun. 70: 59725981.
67. Tai, T. L.,, K. P. O’Rourke,, M. McWeeney,, C. M. Burke,, K. Sheehan, and, M. Barry. 2002 Pneumocystis carinii pneumonia following a second infusion of infliximab. Rheumatology (Oxford) 41: 951952.
68. Traynor, T. R.,, A. C. Herring,, M. E. Dorf,, W. A. Kuziel,, G. B. Toews, and, G. B. Huffnagle. 2002 Differential roles of CC chemokine ligand 2/monocyte chemotactic protein-1 and CCR2 in the development of T1 immunity. J. Immunol. 168: 46594666.
69. Traynor, T. R.,, W. A. Kuziel,, G. B. Toews, and, G. B. Huffnagle. 2000 CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neofor-mans infection. J. Immunol. 164: 20212027.
70. True, D. G.,, M. Penmetcha, and, S. J. Peckham. 2002 Disseminated cryptococcal infection in rheumatoid arthritis treated with methotrexate and infliximab. J. Rheumatol. 29: 15611563.
71. von Boehmer, H. 2005 Mechanisms of suppression by suppressor T cells. Nat. Immunol. 6: 338344.
72. Warris, A.,, A. Bjorneklett, and, P. Gaustad. 2001 Invasive pulmonary aspergillosis associated with infliximab therapy. N. Engl. J. Med. 344: 10991100.
73. Wood, K. L.,, C. A. Hage,, K. S. Knox,, M. B. Kleiman,, A. Sannuti,, R. B. Day,, L. J. Wheat, and, H. L. Twigg, III. 2003 Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am. J. Respir. Crit. Care Med. 167: 12791282.
74. Wuthrich, M.,, H. I. Filutowicz,, T. Warner,, G. S. Deepe, Jr., and, B. S. Klein. 2003 Vaccine immunity to pathogenic fungi overcomes the requirement for CD4 help in exogenous antigen presentation to CD8 + T cells: implications for vaccine development in immune-deficient hosts. J. Exp. Med. 197: 14051416.
75. Zhou, P.,, M. C. Sieve,, J. Bennett,, K. J. Kwon-Chung,, R. P. Tewari,, R. T. Gazzinelli,, A. Sher, and, R. A. Seder. 1995 IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-γ . J. Immunol. 155: 785795.

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