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Immunomodulating effects of antifungal therapy

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Abstract

The action of modern antifungal drugs may not be restricted to their direct fungicidal or fungistatic activity. Recent evidence suggests that antifungals may stimulate or alter the host immune response by mechanisms that may result in enhanced fungal clearance, but with possible increased collateral damage to the host. Dissecting the net impact of antifungal therapy-mediated immunomodulation is difficult because the type and magnitude of these immunostimulatory properties are influenced by the class and type of the drug, the immunologic status of the host, and the specific fungal pathogen. Ultimately, immunopharmacologic considerations may become important in selecting and dosing antifungal therapy for opportunistic mycoses.

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References and Recommended Reading

  1. Richardson MD: Changing patterns and trends in systemic fungal infections. J Antimicrob Chemother 2005, 56(Suppl 1):i5–i11.

    Article  PubMed  CAS  Google Scholar 

  2. Marr KA, Carter RA, Crippa F, et al.: Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002, 34:909–917.

    Article  PubMed  Google Scholar 

  3. Kullberg BJ, Oude Lashof AM, Netea MG: Design of efficacy trials of cytokines in combination with antifungal drugs. Clin Infect Dis 2004, 39(Suppl 4):S218–S223.

    Article  PubMed  Google Scholar 

  4. Ben-Ami R, Lewis RE, Kontoyiannis DP: Immunocompromised hosts: immunopharmacology of modern antifungals. Clin Infect Dis 2008, 47:226–235.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Sato K, Yang XL, Yudate T, et al.: Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses. J Biol Chem 2006, 281:38854–38866.

    Article  PubMed  CAS  Google Scholar 

  7. Netea MG, Gow NA, Munro CA, et al.: Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J Clin Invest 2006, 116:1642–1650.

    Article  PubMed  CAS  Google Scholar 

  8. Bellocchio S, Moretti S, Perruccio K, et al.: TLRs govern neutrophil activity in aspergillosis. J Immunol 2004, 173:7406–7415.

    PubMed  CAS  Google Scholar 

  9. Antachopoulos C, Roilides E: Cytokines and fungal infections. Br J Haematol 2005, 129:583–596.

    Article  PubMed  CAS  Google Scholar 

  10. Hamilton AJ, Holdom MD: Antioxidant systems in the pathogenic fungi of man and their role in virulence. Med Mycol 1999, 37:375–389.

    Article  PubMed  CAS  Google Scholar 

  11. Rappleye CA, Eissenberg LG, Goldman WE: Histoplasma capsulatum alpha-(1,3)-glucan blocks innate immune recognition by the beta-glucan receptor. Proc Natl Acad Sci U S A 2007, 104:1366–1370.

    Article  PubMed  CAS  Google Scholar 

  12. Netea MG, Warris A, Van der Meer JW, et al.: Aspergillus fumigatus evades immune recognition during germination through loss of toll-like receptor-4-mediated signal transduction. J Infect Dis 2003, 188:320–326.

    Article  PubMed  CAS  Google Scholar 

  13. Wheeler RT, Fink GR: A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog 2006, 2:e35.

    Article  PubMed  CAS  Google Scholar 

  14. Gantner BN, Simmons RM, Underhill DM: Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments. EMBO J 2005, 24:1277–1286.

    Article  PubMed  CAS  Google Scholar 

  15. Comera C, Andre K, Laffitte J, et al.: Gliotoxin from Aspergillus fumigatus affects phagocytosis and the organization of the actin cytoskeleton by distinct signalling pathways in human neutrophils. Microbes Infect 2007, 9:47–54.

    Article  PubMed  CAS  Google Scholar 

  16. Casadevall A, Pirofski LA: The damage-response framework of microbial pathogenesis. Nat Rev Microbiol 2003, 1:17–24.

    Article  PubMed  CAS  Google Scholar 

  17. Lionakis MS, Kontoyiannis DP: Glucocorticoids and invasive fungal infections. Lancet 2003, 362:1828–1838.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Stergiopoulou T, Meletiadis J, Roilides E, et al.: Hostdependent patterns of tissue injury in invasive pulmonary aspergillosis. Am J Clin Pathol 2007, 127:349–355.

    Article  PubMed  Google Scholar 

  20. Roilides E, Lyman CA, Filioti J, 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, 46:1974–1976.

    Article  PubMed  CAS  Google Scholar 

  21. Lewis RE, Wiederhold NP, Chi J, et al.: Detection of gliotoxin in experimental and human aspergillosis. Infect Immun 2005, 73:635–637.

    Article  PubMed  CAS  Google Scholar 

  22. Reeves EP, Murphy T, Daly P, Kavanagh K: Amphotericin B enhances the synthesis and release of the immunosuppressive agent gliotoxin from the pulmonary pathogen Aspergillus fumigatus. J Med Microbiol 2004, 53:719–725.

    Article  PubMed  CAS  Google Scholar 

  23. Arning M, Kliche KO, Heer-Sonderhoff AH, Wehmeier A: Infusion-related toxicity of three different amphotericin B formulations and its relation to cytokine plasma levels. Mycoses 1995, 38:459–465.

    Article  PubMed  CAS  Google Scholar 

  24. Cleary JD, Chapman SW, Nolan RL: Pharmacologic modulation of interleukin-1 expression by amphotericin B-stimulated human mononuclear cells. Antimicrob Agents Chemother 1992, 36:977–981.

    PubMed  CAS  Google Scholar 

  25. Sau K, Mambula SS, Latz E, et al.: The antifungal drug amphotericin B promotes inflammatory cytokine release by a Toll-like receptor- and CD14-dependent mechanism. J Biol Chem 2003, 278:37561–37568.

    Article  PubMed  CAS  Google Scholar 

  26. Matthews RC, Rigg G, Hodgetts S, et al.: Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90. Antimicrob Agents Chemother 2003, 47:2208–2216.

    Article  PubMed  CAS  Google Scholar 

  27. Pachl J, Svoboda P, Jacobs F, et al.: A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin Infect Dis 2006, 42:1404–1413.

    Article  PubMed  CAS  Google Scholar 

  28. Cenci E, Mencacci A, Del Sero G, et al.: Induction of protective Th1 responses to Candida albicans by antifungal therapy alone or in combination with an interleukin-4 antagonist. J Infect Dis 1997, 176:217–226.

    Article  PubMed  CAS  Google Scholar 

  29. Simitsopoulou M, Roilides E, Dotis J, et al.: Differential expression of cytokines and chemokines in human monocytes induced by lipid formulations of amphotericin B. Antimicrob Agents Chemother 2005, 49:1397–1403.

    Article  PubMed  CAS  Google Scholar 

  30. Simitsopoulou M, Roilides E, Maloukou A, et al.: Interaction of amphotericin B lipid formulations and triazoles with human polymorphonuclear leucocytes for antifungal activity against Zygomycetes. Mycoses 2008, 51:147–154.

    Article  PubMed  CAS  Google Scholar 

  31. Bellocchio S, Gaziano R, Bozza S, 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, 55:214–222.

    Article  PubMed  CAS  Google Scholar 

  32. Eierman DF, Yagami M, Erme SM, et al.: Endogenously opsonized particles divert prostanoid action from lethal to protective in models of experimental endotoxemia. Proc Natl Acad Sci U S A 1995, 92:2815–2819.

    Article  PubMed  CAS  Google Scholar 

  33. Devine DV, Wong K, Serrano K, et al.: Liposome-complement interactions in rat serum: implications for liposome survival studies. Biochim Biophys Acta 1994, 1191:43–51.

    Article  PubMed  CAS  Google Scholar 

  34. Lewis RE, Chamilos G, Prince RA, Kontoyiannis DP: Pretreatment with empty liposomes attenuates the immunopathology of invasive pulmonary aspergillosis in corticosteroid-immunosuppressed mice. Antimicrob Agents Chemother 2007, 51:1078–1081.

    Article  PubMed  CAS  Google Scholar 

  35. Baltch AL, Smith RP, Franke MA, et al.: Effects of cytokines and fluconazole on the activity of human monocytes against Candida albicans. Antimicrob Agents Chemother 2001, 45:96–104.

    Article  PubMed  CAS  Google Scholar 

  36. Vora S, Purimetla N, Brummer E, Stevens DA: Activity of voriconazole, a new triazole, combined with neutrophils or monocytes against Candida albicans: effect of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Antimicrob Agents Chemother 1998, 42:907–910.

    PubMed  CAS  Google Scholar 

  37. Garcha UK, Brummer E, Stevens DA: Synergy of fluconazole with human monocytes or monocyte-derived macrophages for killing of Candida species. J Infect Dis 1995, 172:1620–1623.

    PubMed  CAS  Google Scholar 

  38. Nosanchuk JD, Cleare W, Franzot SP, Casadevall A: Amphotericin B and fluconazole affect cellular charge, macrophage phagocytosis, and cellular morphology of Cryptococcus neoformans at subinhibitory concentrations. Antimicrob Agents Chemother 1999, 43:233–239.

    Article  PubMed  CAS  Google Scholar 

  39. Shimokawa O, Nakayama H: Increased sensitivity of Candida albicans cells accumulating 14 alpha-methylated sterols to active oxygen: possible relevance to in vivo efficacies of azole antifungal agents. Antimicrob Agents Chemother 1992, 36:1626–1629.

    PubMed  CAS  Google Scholar 

  40. Helmick RA, Fletcher AE, Gardner AM, et al.: Imidazole antibiotics inhibit the nitric oxide dioxygenase function of microbial flavohemoglobin. Antimicrob Agents Chemother 2005, 49:1837–1843.

    Article  PubMed  CAS  Google Scholar 

  41. Mencacci A, Cenci E, Bacci A, et al.: Host immune reactivity determines the efficacy of combination immunotherapy and antifungal chemotherapy in candidiasis. J Infect Dis 2000, 181:686–694.

    Article  PubMed  CAS  Google Scholar 

  42. Clemons KV, Brummer E, Stevens DA: Cytokine treatment of central nervous system infection: efficacy of interleukin-12 alone and synergy with conventional antifungal therapy in experimental cryptococcosis. Antimicrob Agents Chemother 1994, 38:460–464.

    PubMed  CAS  Google Scholar 

  43. Chiller T, Farrokhshad K, Brummer E, Stevens DA: The interaction of human monocytes, monocyte-derived macrophages, and polymorphonuclear neutrophils with caspofungin (MK-0991), an echinocandin, for antifungal activity against Aspergillus fumigatus. Diagn Microbiol Infect Dis 2001, 39:99–103.

    Article  PubMed  CAS  Google Scholar 

  44. 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, 6:383–389.

    Article  PubMed  CAS  Google Scholar 

  45. Taylor PR, Tsoni SV, Willment JA, et al.: Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol 2007, 8:31–38.

    Article  PubMed  CAS  Google Scholar 

  46. 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:e1000227.

    Article  PubMed  CAS  Google Scholar 

  47. Lamaris GA, Lewis RE, Chamilos G, et al.: Caspofunginmediated beta-glucan unmasking and enhancement of human polymorphonuclear neutrophil activity against Aspergillus and non-Aspergillus hyphae. J Infect Dis 2008, 198:186–192.

    Article  PubMed  CAS  Google Scholar 

  48. 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, 198:176–185.

    Article  PubMed  CAS  Google Scholar 

  49. Spellberg B, Fu Y, Edwards JE Jr, Ibrahim AS: Combination therapy with amphotericin B lipid complex and caspofungin acetate of disseminated zygomycosis in diabetic ketoacidotic mice. Antimicrob Agents Chemother 2005, 49:830–832.

    Article  PubMed  CAS  Google Scholar 

  50. Reed C, Bryant R, Ibrahim AS, et al.: Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis 2008, 47:364–371.

    Article  PubMed  CAS  Google Scholar 

  51. Spellberg B, Schwartz J, Fu Y, et al.: Comparison of antifungal treatments for murine fusariosis. J Antimicrob Chemother 2006, 58:973–979.

    Article  PubMed  CAS  Google Scholar 

  52. Bocanegra R, Najvar LK, Hernandez S, et al.: Caspofungin and liposomal amphotericin B therapy of experimental murine scedosporiosis. Antimicrob Agents Chemother 2005, 49:5139–5141.

    Article  PubMed  CAS  Google Scholar 

  53. Kurtz MB, Heath IB, Marrinan J, et al.: Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)-beta-D-glucan synthase. Antimicrob Agents Chemother 1994, 38:1480–1489.

    PubMed  CAS  Google Scholar 

  54. Pappas PG, Bustamante B, Ticona E, et al.: Recombinant interferon- gamma 1b as adjunctive therapy for AIDSrelated acute cryptococcal meningitis. J Infect Dis 2004, 189:2185–2191.

    Article  PubMed  CAS  Google Scholar 

  55. Larsen RA, Pappas PG, Perfect J, et al.: Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis. Antimicrob Agents Chemother 2005, 49:952–958.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Dimitrios P. Kontoyiannis.

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Leventakos, K., Ben-Ami, R., Lewis, R.E. et al. Immunomodulating effects of antifungal therapy. Curr Fungal Infect Rep 3, 243–250 (2009). https://doi.org/10.1007/s12281-009-0034-6

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