Skip to main content

Immunomodulatory Properties of Antifungal Agents on Immune Functions of the Host

  • Chapter
  • First Online:
Principles and Practice of Transplant Infectious Diseases

Abstract

The first line and the most effective form of antifungal host defense are comprised by phagocytes, particularly neutrophils and monocytes/macrophages that play a central role in local containment of infection and prevent systemic dissemination. These immune cells are also exposed to antifungal drugs while patients undergo systemic antifungal therapy. In the phagocyte-fungus-antifungal drug interplay, drugs including amphotericin B formulations, azoles, and echinocandins may directly interact with phagocytes through specific pattern recognition receptors, leading to altered antifungal activities. Drugs, through modulation of fungal virulence, may initiate different immune response pathways in the phagocytes, leading to upregulation of gene expression for a pro-inflammatory response or to antifungal synergism versus antagonism. Additionally, indirect modulation of mononuclear innate immune cell behavior by pretreatment with cytokines and exposure to antifungal agents has shown a promising outcome for combined drug-cytokine therapy in certain difficult to treat life-threatening invasive fungal diseases. In this chapter, the immunomodulatory role of antifungal agents on phagocytic immune cells in response to fungal stimulation is presented. The underlying mechanisms and the potential clinical relevance of such antifungal effects are also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Walsh TJ, Groll A, Hiemenz J, Fleming R, Roilides E, Anaissie E. Infections due to emerging and uncommon medically important fungal pathogens. Clin Microbiol Infect. 2004;10(Suppl 1):48–66.

    Article  PubMed  Google Scholar 

  2. Miceli MH, Lee SA. Emerging moulds: epidemiological trends and antifungal resistance. Mycoses. 2011;54(6):e666–78.

    Article  PubMed  Google Scholar 

  3. Munoz P, Fernandez NS, Farinas MC. Epidemiology and risk factors of infections after solid organ transplantation. Enferm Infecc Microbiol Clin. 2012;30(Suppl 2):10–8.

    Article  PubMed  Google Scholar 

  4. Neofytos D, Fishman JA, Horn D, Anaissie E, Chang CH, Olyaei A, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis. 2012;12(3):220–9.

    Article  Google Scholar 

  5. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101–11.

    Article  PubMed  Google Scholar 

  6. Lanternier F, Sun HY, Ribaud P, Singh N, Kontoyiannis DP, Lortholary O. Mucormycosis in organ and stem cell transplant recipients. Clin Infect Dis. 2012;54(11):1629–36.

    Article  Google Scholar 

  7. Quan C, Spellberg B. Mucormycosis, pseudallescheriasis, and other uncommon mold infections. Proc Am Thorac Soc. 2010;7(3):210–5.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pagano L, Akova M, Dimopoulos G, Herbrecht R, Drgona L, Blijlevens N. Risk assessment and prognostic factors for mould-related diseases in immunocompromised patients. J Antimicrob Chemother. 2011;66(Suppl 1):i5–14.

    Article  CAS  PubMed  Google Scholar 

  9. Anderson JB. Evolution of antifungal-drug resistance: mechanisms and pathogen fitness. Nat Rev Microbiol. 2005;3(7):547–56.

    Article  CAS  PubMed  Google Scholar 

  10. Morschhauser J. Regulation of multidrug resistance in pathogenic fungi. Fungal Genet Biol. 2010;47(2):94–106.

    Article  PubMed  CAS  Google Scholar 

  11. Joly S, Sutterwala FS. Fungal pathogen recognition by the NLRP3 inflammasome. Virulence. 2010;1(4):276–80.

    Article  PubMed  Google Scholar 

  12. Yamamoto M, Takeda K. Current views of toll-like receptor signaling pathways. Gastroenterol Res Pract. 2010;2010:240365.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Netea MG, Van der Meer JW, Kullberg BJ. Role of the dual interaction of fungal pathogens with pattern recognition receptors in the activation and modulation of host defence. Clin Microbiol Infect. 2006;12(5):404–9.

    Article  CAS  PubMed  Google Scholar 

  14. Willment JA, Brown GD. C-type lectin receptors in antifungal immunity. Trends Microbiol. 2008;16(1):27–32.

    Article  CAS  PubMed  Google Scholar 

  15. Vautier S, Sousa Mda G, Brown GD. C-type lectins, fungi and Th17 responses. Cytokine Growth Factor Rev. 2010;21(6):405–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Naglik JR, Moyes D. Epithelial cell innate response to Candida albicans. Adv Dent Res. 2011;23(1):50–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. van de Veerdonk FL, Kullberg BJ, van der Meer JW, Gow NA, Netea MG. Host-microbe interactions: innate pattern recognition of fungal pathogens. Curr Opin Microbiol. 2008;11(4):305–12.

    Article  PubMed  CAS  Google Scholar 

  19. Gallin JI, Zarember K. Lessons about the pathogenesis and management of aspergillosis from studies in chronic granulomatous disease. Trans Am Clin Climatol Assoc. 2007;118:175–85.

    PubMed  PubMed Central  Google Scholar 

  20. Odell EW, Segal AW. Killing of pathogens associated with chronic granulomatous disease by the non-oxidative microbicidal mechanisms of human neutrophils. J Med Microbiol. 1991;34(3):129–35.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. Hasenberg M, Behnsen J, Krappmann S, Brakhage A, Gunzer M. Phagocyte responses towards Aspergillus fumigatus. Int J Med Microbiol. 2011;301(5):436–44.

    Article  CAS  PubMed  Google Scholar 

  23. Fournier BM, Parkos CA. The role of neutrophils during intestinal inflammation. Mucosal Immunol. 2012;5(4):354–66.

    Article  CAS  PubMed  Google Scholar 

  24. Savina A, Amigorena S. Phagocytosis and antigen presentation in dendritic cells. Immunol Rev. 2007;219:143–56.

    Article  CAS  PubMed  Google Scholar 

  25. van Vliet SJ, den Dunnen J, Gringhuis SI, Geijtenbeek TB, van Kooyk Y. Innate signaling and regulation of Dendritic cell immunity. Curr Opin Immunol. 2007;19(4):435–40.

    Article  PubMed  CAS  Google Scholar 

  26. Zelante T, Bozza S, De Luca A, D'Angelo C, Bonifazi P, Moretti S, et al. Th17 cells in the setting of Aspergillus infection and pathology. Med Mycol. 2009;47(Suppl 1):S162–9.

    Article  CAS  PubMed  Google Scholar 

  27. Villar CC, Dongari-Bagtzoglou A. Immune defence mechanisms and immunoenhancement strategies in oropharyngeal candidiasis. Expert Rev Mol Med. 2008;10:e29.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Janes MR, Fruman DA. Immune regulation by rapamycin: moving beyond T cells. Sci Signal. 2009;2(67):pe25.

    Article  PubMed  Google Scholar 

  29. Yamaguchi H, Abe S, Tokuda Y. Immunomodulating activity of antifungal drugs. Ann N Y Acad Sci. 1993;685:447–57.

    Article  CAS  PubMed  Google Scholar 

  30. Stevens DA, Kullberg BJ, Brummer E, Casadevall A, Netea MG, Sugar AM. Combined treatment: antifungal drugs with antibodies, cytokines or drugs. Med Mycol. 2000;38(Suppl 1):305–15.

    Article  CAS  PubMed  Google Scholar 

  31. Hamad M. Antifungal immunotherapy and immunomodulation: a double-hitter approach to deal with invasive fungal infections. Scand J Immunol. 2008;67(6):533–43.

    Article  CAS  PubMed  Google Scholar 

  32. Laniado-Laborin R, Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Rev Iberoam Micol. 2009;26(4):223–7.

    Article  PubMed  Google Scholar 

  33. Sau K, Mambula SS, Latz E, Henneke P, Golenbock DT, Levitz SM. The antifungal drug amphotericin B promotes inflammatory cytokine release by a Toll-like receptor- and CD14-dependent mechanism. J Biol Chem. 2003;278(39):37561–8.

    Article  CAS  PubMed  Google Scholar 

  34. Razonable RR, Henault M, Lee LN, Laethem C, Johnston PA, Watson HL, et al. Secretion of proinflammatory cytokines and chemokines during amphotericin B exposure is mediated by coactivation of toll-like receptors 1 and 2. Antimicrob Agents Chemother. 2005;49(4):1617–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Matsuo K, Hotokezaka H, Ohara N, Fujimura Y, Yoshimura A, Okada Y, et al. Analysis of amphotericin B-induced cell signaling with chemical inhibitors of signaling molecules. Microbiol Immunol. 2006;50(4):337–47.

    Article  CAS  PubMed  Google Scholar 

  36. Bellocchio S, Gaziano R, Bozza S, Rossi G, Montagnoli C, Perruccio K, et al. Liposomal amphotericin B activates antifungal resistance with reduced toxicity by diverting Toll-like receptor signalling from TLR-2 to TLR-4. J Antimicrob Chemother. 2005;55(2):214–22.

    Article  CAS  PubMed  Google Scholar 

  37. Cleary JD, Rogers PD, Chapman SW. Differential transcription factor expression in human mononuclear cells in response to amphotericin B: identification with complementary DNA microarray technology. Pharmacotherapy. 2001;21(9):1046–54.

    Article  CAS  PubMed  Google Scholar 

  38. Turtinen LW, Bremer LA, Prall DN, Schwartzhoff J, Hartsel SC. Distinct cytokine release profiles from human endothelial and THP-1 macrophage-like cells exposed to different amphotericin B formulations. Immunopharmacol Immunotoxicol. 2005;27(1):85–93.

    Article  CAS  PubMed  Google Scholar 

  39. Turtinen LW, Croswell A, Obr A. Microarray analysis of amphotericin B-treated THP-1 monocytic cells identifies unique gene expression profiles among lipid and non-lipid drug formulations. J Chemother. 2008;20(3):327–35.

    Article  CAS  PubMed  Google Scholar 

  40. Turtinen LW, Prall DN, Bremer LA, Nauss RE, Hartsel SC. Antibody array-generated profiles of cytokine release from THP-1 leukemic monocytes exposed to different amphotericin B formulations. Antimicrob Agents Chemother. 2004;48(2):396–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Simitsopoulou M, Roilides E, Dotis J, Dalakiouridou M, Dudkova F, Andreadou E, et al. Differential expression of cytokines and chemokines in human monocytes induced by lipid formulations of amphotericin B. Antimicrob Agents Chemother. 2005;49(4):1397–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rogers PD, Jenkins JK, Chapman SW, Ndebele K, Chapman BA, Cleary JD. Amphotericin B activation of human genes encoding for cytokines. J Infect Dis. 1998;178(6):1726–33.

    Article  CAS  PubMed  Google Scholar 

  43. Rogers PD, Kramer RE, Chapman SW, Cleary JD. Amphotericin B-induced interleukin-1beta expression in human monocytic cells is calcium and calmodulin dependent. J Infect Dis. 1999;180(4):1259–66.

    Article  CAS  PubMed  Google Scholar 

  44. Rogers PD, Pearson MM, Cleary JD, Sullivan DC, Chapman SW. Differential expression of genes encoding immunomodulatory proteins in response to amphotericin B in human mononuclear cells identified by cDNA microarray analysis. J Antimicrob Chemother. 2002;50(6):811–7.

    Article  CAS  PubMed  Google Scholar 

  45. Rogers PD, Stiles JK, Chapman SW, Cleary JD. Amphotericin B induces expression of genes encoding chemokines and cell adhesion molecules in the human monocytic cell line THP-1. J Infect Dis. 2000;182(4):1280–3.

    Article  CAS  PubMed  Google Scholar 

  46. Saxena S, Bhatnagar PK, Ghosh PC, Sarma PU. Effect of amphotericin B lipid formulation on immune response in aspergillosis. Int J Pharm. 1999;188(1):19–30.

    Article  CAS  PubMed  Google Scholar 

  47. Simitsopoulou M, Roilides E, Georgiadou E, Paliogianni F, Walsh TJ. Differential transcriptional profiles induced by amphotericin B formulations on human monocytes during response to hyphae of Aspergillus fumigatus. Med Mycol. 2011;49(2):176–85.

    Article  CAS  PubMed  Google Scholar 

  48. Martin E, Stuben A, Gorz A, Weller U, Bhakdi S. Novel aspect of amphotericin B action: accumulation in human monocytes potentiates killing of phagocytosed Candida albicans. Antimicrob Agents Chemother. 1994;38(1):13–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jahn B, Rampp A, Dick C, Jahn A, Palmer M, Bhakdi S. Accumulation of amphotericin B in human macrophages enhances activity against Aspergillus fumigatus conidia: quantification of conidial kill at the single-cell level. Antimicrob Agents Chemother. 1998;42(10):2569–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pascual A, Garcia I, Conejo C, Perea EJ. Uptake and intracellular activity of fluconazole in human polymorphonuclear leukocytes. Antimicrob Agents Chemother. 1993;37(2):187–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Frank U, Greiner M, Engels I, Daschner FD. Effects of caspofungin (MK-0991) and anidulafungin (LY303366) on phagocytosis, oxidative burst and killing of Candida albicans by human phagocytes. Eur J Clin Microbiol Infect Dis. 2004;23(9):729–31.

    Article  CAS  PubMed  Google Scholar 

  52. Baltch AL, Bopp LH, Smith RP, Ritz WJ, Carlyn CJ, Michelsen PB. Effects of voriconazole, granulocyte-macrophage colony-stimulating factor, and interferon gamma on intracellular fluconazole-resistant Candida glabrata and Candida krusei in human monocyte-derived macrophages. Diagn Microbiol Infect Dis. 2005;52(4):299–304.

    Article  CAS  PubMed  Google Scholar 

  53. Baltch AL, Bopp LH, Smith RP, Ritz WJ, Michelsen PB. Anticandidal effects of voriconazole and caspofungin, singly and in combination, against Candida glabrata, extracellularly and intracellularly in granulocyte-macrophage colony stimulating factor (GM-CSF)-activated human monocytes. J Antimicrob Chemother. 2008;62(6):1285–90.

    Article  CAS  PubMed  Google Scholar 

  54. Ballesta S, Garcia I, Perea EJ, Pascual A. Uptake and intracellular activity of voriconazole in human polymorphonuclear leucocytes. J Antimicrob Chemother. 2005;55(5):785–7.

    Article  CAS  PubMed  Google Scholar 

  55. Bopp LH, Baltch AL, Ritz WJ, Michelsen PB, Smith RP. Antifungal effect of voriconazole on intracellular Candida glabrata, Candida krusei and Candida parapsilosis in human monocyte-derived macrophages. J Med Microbiol. 2006;55(Pt 7):865–70.

    Article  CAS  PubMed  Google Scholar 

  56. Tohyama M, Kawakami K, Saito A. Anticryptococcal effect of amphotericin B is mediated through macrophage production of nitric oxide. Antimicrob Agents Chemother. 1996;40(8):1919–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dotis J, Simitsopoulou M, Dalakiouridou M, Konstantinou T, Panteliadis C, Walsh TJ, et al. Amphotericin B formulations variably enhance antifungal activity of human neutrophils and monocytes against Fusarium solani: comparison with Aspergillus fumigatus. J Antimicrob Chemother. 2008;61(4):810–7.

    Article  CAS  PubMed  Google Scholar 

  58. Dotis J, Simitsopoulou M, Dalakiouridou M, Konstantinou T, Taparkou A, Kanakoudi-Tsakalidou F, et al. Effects of lipid formulations of amphotericin B on activity of human monocytes against Aspergillus fumigatus. Antimicrob Agents Chemother. 2006;50(3):868–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Roilides E, Lyman CA, Armstrong D, Stergiopoulou T, Petraitiene R, Walsh TJ. Deoxycholate amphotericin B and amphotericin B lipid complex exert additive antifungal activity in combination with pulmonary alveolar macrophages against Fusarium solani. Mycoses. 2006;49(2):109–13.

    Article  CAS  PubMed  Google Scholar 

  60. Simitsopoulou M, Roilides E, Maloukou A, Gil-Lamaignere C, Walsh TJ. Interaction of amphotericin B lipid formulations and triazoles with human polymorphonuclear leucocytes for antifungal activity against Zygomycetes. Mycoses. 2008;51(2):147–54.

    Article  CAS  PubMed  Google Scholar 

  61. Roilides E, Lyman CA, Filioti J, Akpogheneta O, Sein T, Lamaignere CG, et al. Amphotericin B formulations exert additive antifungal activity in combination with pulmonary alveolar macrophages and polymorphonuclear leukocytes against Aspergillus fumigatus. Antimicrob Agents Chemother. 2002;46(6):1974–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gil-Lamaignere C, Roilides E, Maloukou A, Georgopoulou I, Petrikkos G, Walsh TJ. Amphotericin B lipid complex exerts additive antifungal activity in combination with polymorphonuclear leucocytes against Scedosporium prolificans and Scedosporium apiospermum. J Antimicrob Chemother. 2002;50(6):1027–30.

    Article  CAS  PubMed  Google Scholar 

  63. Swenson CE, Perkins WR, Roberts P, Ahmad I, Stevens R, Stevens DA, et al. In vitro and in vivo antifungal activity of amphotericin B lipid complex: are phospholipases important? Antimicrob Agents Chemother. 1998;42(4):767–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Simitsopoulou M, Roilides E, Paliogianni F, Likartsis C, Ioannidis J, Kanellou K, et al. Immunomodulatory effects of voriconazole on monocytes challenged with Aspergillus fumigatus: differential role of Toll-like receptors. Antimicrob Agents Chemother. 2008;52(9):3301–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Salvenmoser S, Seidler MJ, Dalpke A, Muller FM. Effects of caspofungin, Candida albicans and Aspergillus fumigatus on toll-like receptor 9 of GM-CSF-stimulated PMNs. FEMS Immunol Med Microbiol. 2010;60(1):74–7.

    Article  CAS  PubMed  Google Scholar 

  66. Choi JH, Kwon EY, Park CM, Choi SM, Lee DG, Yoo JH, et al. Immunomodulatory effects of antifungal agents on the response of human monocytic cells to Aspergillus fumigatus conidia. Med Mycol. 2010;48(5):704–9.

    Article  CAS  PubMed  Google Scholar 

  67. Kimberg M, Brown GD. Dectin-1 and its role in antifungal immunity. Med Mycol. 2008;46(7):631–6.

    Article  CAS  PubMed  Google Scholar 

  68. Murphy EA, Davis JM, Carmichael MD. Immune modulating effects of beta-glucan. Curr Opin Clin Nutr Metab Care. 2010;13(6):656–61.

    Article  CAS  PubMed  Google Scholar 

  69. Hohl TM, Feldmesser M, Perlin DS, Pamer EG. Caspofungin modulates inflammatory responses to Aspergillus fumigatus through stage-specific effects on fungal beta-glucan exposure. J Infect Dis. 2008;198(2):176–85.

    Article  CAS  PubMed  Google Scholar 

  70. Lamaris GA, Lewis RE, Chamilos G, May GS, Safdar A, Walsh TJ, et al. Caspofungin-mediated beta-glucan unmasking and enhancement of human polymorphonuclear neutrophil activity against Aspergillus and non-Aspergillus hyphae. J Infect Dis. 2008;198(2):186–92.

    Article  CAS  PubMed  Google Scholar 

  71. Wheeler RT, Kombe D, Agarwala SD, Fink GR. Dynamic, morphotype-specific Candida albicans beta-glucan exposure during infection and drug treatment. PLoS Pathog. 2008;4(12):e1000227.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Ruiz-Herrera J, Elorza MV, Valentin E, Sentandreu R. Molecular organization of the cell wall of Candida albicans and its relation to pathogenicity. FEMS Yeast Res. 2006;6(1):14–29.

    Article  CAS  PubMed  Google Scholar 

  73. Shibata N, Suzuki A, Kobayashi H, Okawa Y. Chemical structure of the cell-wall mannan of Candida albicans serotype A and its difference in yeast and hyphal forms. Biochem J. 2007;404(3):365–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wellington M, Dolan K, Krysan DJ. Live Candida albicans suppresses production of reactive oxygen species in phagocytes. Infect Immun. 2009;77(1):405–13.

    Article  CAS  PubMed  Google Scholar 

  75. Tullio V, Mandras N, Scalas D, Allizond V, Banche G, Roana J, et al. Synergy of caspofungin with human polymorphonuclear granulocytes for killing Candida albicans. Antimicrob Agents Chemother. 2010;54(9):3964–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Allizond V, Banche G, Giacchino F, Merlino C, Scalas D, Tullio V, et al. Candida albicans infections in renal transplant recipients: effect of caspofungin on polymorphonuclear cells. Antimicrob Agents Chemother. 2011;55(12):5936–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Choi JH, Brummer E, Stevens DA. Combined action of micafungin, a new echinocandin, and human phagocytes for antifungal activity against Aspergillus fumigatus. Microbes Infect. 2004;6(4):383–9.

    Article  CAS  PubMed  Google Scholar 

  78. Anaissie EJ. Diagnosis and therapy of fungal infection in patients with leukemia--new drugs and immunotherapy. Best Pract Res Clin Haematol. 2008;21(4):683–90.

    Article  CAS  PubMed  Google Scholar 

  79. Gullo A. Invasive fungal infections: the challenge continues. Drugs. 2009;69(Suppl 1):65–73.

    Article  PubMed  Google Scholar 

  80. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351(14):1391–402.

    Article  CAS  PubMed  Google Scholar 

  81. Mavor AL, Thewes S, Hube B. Systemic fungal infections caused by Candida species: epidemiology, infection process and virulence attributes. Curr Drug Targets. 2005;6(8):863–74.

    Article  CAS  PubMed  Google Scholar 

  82. Ramage G, Saville SP, Thomas DP, Lopez-Ribot JL. Candida biofilms: an update. Eukaryot Cell. 2005;4(4):633–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mikulska M, Bassetti M, Ratto S, Viscoli C. Invasive candidiasis in non-hematological patients. Mediterr J Hematol Infect Dis. 2011;3(1):e2011007.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Kuhn DM, George T, Chandra J, Mukherjee PK, Ghannoum MA. Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins. Antimicrob Agents Chemother. 2002;46(6):1773–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Shuford JA, Piper KE, Steckelberg JM, Patel R. In vitro biofilm characterization and activity of antifungal agents alone and in combination against sessile and planktonic clinical Candida albicans isolates. Diagn Microbiol Infect Dis. 2007;57(3):277–81.

    Article  CAS  PubMed  Google Scholar 

  86. Tobudic S, Kratzer C, Lassnigg A, Presterl E. Antifungal susceptibility of Candida albicans in biofilms. Mycoses. 2012;55(3):199–204.

    Article  PubMed  Google Scholar 

  87. Chandra J, McCormick TS, Imamura Y, Mukherjee PK, Ghannoum MA. Interaction of Candida albicans with adherent human peripheral blood mononuclear cells increases C. albicans biofilm formation and results in differential expression of pro- and anti-inflammatory cytokines. Infect Immun. 2007;75(5):2612–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Katragkou A, Kruhlak MJ, Simitsopoulou M, Chatzimoschou A, Taparkou A, Cotten CJ, et al. Interactions between human phagocytes and Candida albicans biofilms alone and in combination with antifungal agents. J Infect Dis. 2010;201(12):1941–9.

    Article  CAS  PubMed  Google Scholar 

  89. Katragkou A, Chatzimoschou A, Simitsopoulou M, Georgiadou E, Roilides E. Additive antifungal activity of anidulafungin and human neutrophils against Candida parapsilosis biofilms. J Antimicrob Chemother. 2011;66(3):588–91.

    Article  CAS  PubMed  Google Scholar 

  90. Stergiopoulou T, Meletiadis J, Sein T, Papaioannidou P, Tsiouris I, Roilides E, et al. Isobolographic analysis of pharmacodynamic interactions between antifungal agents and ciprofloxacin against Candida albicans and Aspergillus fumigatus. Antimicrob Agents Chemother. 2008;52(6):2196–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Stergiopoulou T, Meletiadis J, Sein T, Papaioannidou P, Tsiouris I, Roilides E, et al. Comparative pharmacodynamic interaction analysis between ciprofloxacin, moxifloxacin and levofloxacin and antifungal agents against Candida albicans and Aspergillus fumigatus. J Antimicrob Chemother. 2009;63(2):343–8.

    Article  CAS  PubMed  Google Scholar 

  92. Stergiopoulou T, Meletiadis J, Sein T, Papaioannidou P, Walsh TJ, Roilides E. Synergistic interaction of the triple combination of amphotericin B, ciprofloxacin, and polymorphonuclear neutrophils against Aspergillus fumigatus. Antimicrob Agents Chemother. 2011;55(12):5923–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chiller T, Farrokhshad K, Brummer E, Stevens DA. Effect of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on polymorphonuclear neutrophils, monocytes or monocyte-derived macrophages combined with voriconazole against Cryptococcus neoformans. Med Mycol. 2002;40(1):21–6.

    Article  CAS  PubMed  Google Scholar 

  94. Vora S, Chauhan S, Brummer E, Stevens DA. Activity of voriconazole combined with neutrophils or monocytes against Aspergillus fumigatus: effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Antimicrob Agents Chemother. 1998;42(9):2299–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Herrmann JL, Dubois N, Fourgeaud M, Basset D, Lagrange PH. Synergic inhibitory activity of amphotericin-B and gamma interferon against intracellular Cryptococcus neoformans in murine macrophages. J Antimicrob Chemother. 1994;34(6):1051–8.

    Article  CAS  PubMed  Google Scholar 

  96. Graybill JR, Bocanegra R, Luther M. Antifungal combination therapy with granulocyte colony-stimulating factor and fluconazole in experimental disseminated candidiasis. Eur J Clin Microbiol Infect Dis. 1995;14(8):700–3.

    Article  CAS  PubMed  Google Scholar 

  97. Mencacci A, Cenci E, Bacci A, Bistoni F, Romani L. Host immune reactivity determines the efficacy of combination immunotherapy and antifungal chemotherapy in candidiasis. J Infect Dis. 2000;181(2):686–94.

    Article  CAS  PubMed  Google Scholar 

  98. Patera AC, Menzel F, Jackson C, Brieland JK, Halpern J, Hare R, et al. Effect of granulocyte colony-stimulating factor combination therapy on efficacy of posaconazole (SCH56592) in an inhalation model of murine pulmonary aspergillosis. Antimicrob Agents Chemother. 2004;48(8):3154–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Rodriguez MM, Pastor FJ, Calvo E, Salas V, Sutton DA, Guarro J. Correlation of in vitro activity, serum levels, and in vivo efficacy of posaconazole against Rhizopus microsporus in a murine disseminated infection. Antimicrob Agents Chemother. 2009;53(12):5022–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Graybill JR, Bocanegra R, Najvar LK, Loebenberg D, Luther MF. Granulocyte colony-stimulating factor and azole antifungal therapy in murine aspergillosis: role of immune suppression. Antimicrob Agents Chemother. 1998;42(10):2467–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Simitsopoulou M, Gil-Lamaignere C, Avramidis N, Maloukou A, Lekkas S, Havlova E, et al. Antifungal activities of posaconazole and granulocyte-macrophage colony-stimulating factor ex vivo and in mice with disseminated infection due to Scedosporium prolificans. Antimicrob Agents Chemother. 2004;48(10):3801–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Romani L. Immunity to fungal infections. Nat Rev Immunol. 2004;4(1):1–23.

    Article  PubMed  CAS  Google Scholar 

  103. Blanco JL, Garcia ME. Immune response to fungal infections. Vet Immunol Immunopathol. 2008;125(1-2):47–70.

    Article  CAS  PubMed  Google Scholar 

  104. Roilides E, Lyman CA, Panagopoulou P, Chanock S. Immunomodulation of invasive fungal infections. Infect Dis Clin North Am. 2003;17(1):193–219.

    Article  PubMed  Google Scholar 

  105. Roilides E, Walsh T. Recombinant cytokines in augmentation and immunomodulation of host defenses against Candida spp. Med Mycol. 2004;42(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  106. Steinbach WJ, Stevens DA. Review of newer antifungal and immunomodulatory strategies for invasive aspergillosis. Clin Infect Dis. 2003;37(Suppl 3):S157–87.

    Article  CAS  PubMed  Google Scholar 

  107. Antachopoulos C, Roilides E. Cytokines and fungal infections. Br J Haematol. 2005;129(5):583–96.

    Article  CAS  PubMed  Google Scholar 

  108. Safdar A, Shelburne SA, Evans SE, Dickey BF. Inhaled therapeutics for prevention and treatment of pneumonia. Expert Opin Drug Saf. 2009;8(4):435–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sorrell TC, Chen SC. Fungal-derived immune modulating molecules. Adv Exp Med Biol. 2009;666:108–20.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Emmanuel Roilides .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Simitsopoulou, M., Roilides, E. (2019). Immunomodulatory Properties of Antifungal Agents on Immune Functions of the Host. In: Safdar, A. (eds) Principles and Practice of Transplant Infectious Diseases. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-9034-4_53

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9034-4_53

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-9032-0

  • Online ISBN: 978-1-4939-9034-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics