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Review article: Biomedical intelligence

Vol. 146 No. 3738 (2016)

Host response to fungal infections – how immunology and host genetics could help to identify and treat patients at risk

  • Nina Khanna
  • Claudia Stuehler
  • Anna Lünemann
  • Agnieszka Wójtowicz
  • Pierre-Yves Bochud
  • Salomé Leibundgut-Landmann
DOI
https://doi.org/10.4414/smw.2016.14350
Cite this as:
Swiss Med Wkly. 2016;146:w14350
Published
11.09.2016

Summary

In spite of the ever-increasing incidence and poor outcome of invasive fungal infections in immune compromised patients, there is currently no reliable method to accurately predict the risk, to monitor the outcome and to treat these infections. Protective immunity against Candida and Aspergillus depends on a highly coordinated interaction between the innate and adaptive immune systems. Genetic and immunological defects in components of these networks result in increased risk of invasive fungal infections among patients undergoing chemotherapy or transplant recipients.

We review the most important genetic and immunological factors that influence human susceptibility to Candida and Aspergillus infections and discuss the potential role of basic research to promote precision medicine for infectious diseases. We discuss how immunogenetic studies can help to provide tools for improved identification of high-risk patients and the development of tailored antifungal therapies.

References

  1. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med. 2012;4:165rv113.
  2. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091–101.
  3. Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50:1091–100.
  4. Marr KA. Fungal infections in hematopoietic stem cell transplant recipients. Med Mycol. 2008;46:293–302.
  5. Pagano L, Caira M, Nosari A, Van Lint MT, Candoni A, Offidani M, et al. Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study-Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne. Clin Infect Dis. 2007;45:1161–70.
  6. Patterson TF, Kirkpatrick WR, White M, Hiemenz JW, Wingard JR, Dupont B, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group. Medicine (Baltimore). 2000;79:250–60.
  7. Singh N, Avery RK, Munoz P, Pruett TL, Alexander B, Jacobs R, et al. Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients. Clin Infect Dis. 2003;36:46–52.
  8. Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91:1068–75.
  9. Nivoix Y, Velten M, Letscher-Bru V, Moghaddam A, Natarajan-Ame S, Fohrer C, et al. Factors associated with overall and attributable mortality in invasive aspergillosis. Clin Infect Dis. 2008;47:1176–84.
  10. Upton A, Kirby KA, Carpenter P, Boeckh M, Marr KA. Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality. Clin Infect Dis. 2007;44:531–40.
  11. Steinbach WJ, Marr KA, Anaissie EJ, Azie N, Quan SP, Meier-Kriesche HU, et al. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Infec.t 2012;65:453–64.
  12. Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326:845–51.
  13. Trifilio SM, Bennett CL, Yarnold PR, McKoy JM, Parada J, Mehta J, et al. Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy. Bone Marrow Transplant. 2007;39:425–9.
  14. Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356:335–47.
  15. Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010;116:5111–8.
  16. Pfaller MA, Diekema DJ. Rare and emerging opportunistic fungal pathogens: concern for resistance beyond Candida albicans and Aspergillus fumigatus. J Clin Microbiol. 2004;42:4419–31.
  17. Bitar D, Van Cauteren D, Lanternier F, Dannaoui E, Che D, Dromer F, et al. Increasing incidence of zygomycosis (mucormycosis), France, 1997–2006. Emerg Infect Dis. 2009;15:1395–401.
  18. Kontoyiannis DP, Lionakis MS, Lewis RE, Chamilos G, Healy M, Perego C, et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis. 2005;191:1350–60.
  19. Pagano L, Offidani M, Fianchi L, Nosari A, Candoni A, Piccardi M, et al. Mucormycosis in hematologic patients. Haematologica. 2004;89:207–14.
  20. Steinmann J, Hamprecht A, Vehreschild MJ, Cornely OA, Buchheidt D, Spiess B, et al. Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany. J Antimicrob Chemother. 2015;70:1522–6.
  21. de Bono JS, Ashworth A. Translating cancer research into targeted therapeutics. Nature. 2010;467:543–9.
  22. Bahcall O. Precision medicine. Nature. 2015;526:335.
  23. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015,372:793–5.
  24. Oliveira-Coelho A, Rodrigues F, Campos A, Jr., Lacerda JF, Carvalho A, Cunha C. Paving the way for predictive diagnostics and personalized treatment of invasive aspergillosis. Front Microbiol. 2015;6:411.
  25. Lionakis MS. New insights into innate immune control of systemic candidiasis. Med Mycol. 2014;52:555–64.
  26. Romani L. Immunity to fungal infections. Nat Rev Immunol. 2004;4:1–23.
  27. Brown GD. Innate antifungal immunity: the key role of phagocytes. Annu Rev Immunol. 2011;29:1–21.
  28. Osorio F, Reis e Sousa C. Myeloid C-type lectin receptors in pathogen recognition and host defense. Immunity. 2011;34:651–64.
  29. Plato A, Hardison SE, Brown GD. Pattern recognition receptors in antifungal immunity. Semin Immunopathol. 2015;37:97–106.
  30. Hardison SE, Brown GD. C-type lectin receptors orchestrate antifungal immunity. Nat Immunol. 2012;13:817–22.
  31. Romani L. Immunity to fungal infections. Nat Rev Immunol. 2011;11:275–88.
  32. Netea MG, Gow NA, Joosten LA, Verschueren I, van der Meer JW, Kullberg BJ. Variable recognition of Candida albicans strains by TLR4 and lectin recognition receptors. Med Mycol. 2010;48:897-903.
  33. Marakalala MJ, Vautier S, Potrykus J, Walker LA, Shepardson KM, Hopke A, et al. Differential adaptation of Candida albicans in vivo modulates immune recognition by dectin-1. PLoS Pathog. 2013;9:e1003315.
  34. Gaziano R, Bozza S, Bellocchio S, Perruccio K, Montagnoli C, Pitzurra L, et al. Anti-Aspergillus fumigatus efficacy of pentraxin 3 alone and in combination with antifungals. Antimicrob Agents Chemother. 2004;48:4414–21.
  35. Gessner MA, Werner JL, Lilly LM, Nelson MP, Metz AE, Dunaway CW, et al. Dectin-1-dependent interleukin-22 contributes to early innate lung defense against Aspergillus fumigatus. Infect Immun. 2012;80:410–17.
  36. Kaur S, Gupta VK, Thiel S, Sarma PU, Madan T. Protective role of mannan-binding lectin in a murine model of invasive pulmonary aspergillosis. Clin Exp Immunol. 2007;148:382–9.
  37. Lo Giudice P, Campo S, Verdoliva A, Rivieccio V, Borsini F, De Santis R, et al. Efficacy of PTX3 in a rat model of invasive aspergillosis. Antimicrob Agents Chemother. 2010;54:4513–5.
  38. Marra E, Sousa VL, Gaziano R, Pacello ML, Arseni B, Aurisicchio L, et al. Efficacy of PTX3 and posaconazole combination in a rat model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2014;58:6284–6.
  39. Werner JL, Metz AE, Horn D, Schoeb TR, Hewitt MM, Schwiebert LM, et al. Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus. J Immunol. 2009;182:4938–46.
  40. Feldmesser M. Role of neutrophils in invasive aspergillosis. Infect Immun. 2006;74:6514–6.
  41. Branzk N, Lubojemska A, Hardison SE, Wang Q, Gutierrez MG, Brown GD, et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol. 2014;15:1017–25.
  42. Bianchi M, Hakkim A, Brinkmann V, Siler U, Seger RA, Zychlinsky A, et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009;114:2619–22.
  43. Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009;5:e1000639.
  44. Taylor PR, Roy S, Leal SM, Jr., Sun Y, Howell SJ, Cobb BA, et al. Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORgammat and dectin-2. Nat Immunol. 2013;15:143–51.
  45. Scapini P, Cassatella MA. Social networking of human neutrophils within the immune system. Blood. 2014;124:710–9.
  46. Wozniok I, Hornbach A, Schmitt C, Frosch M, Einsele H, Hube B, et al. Induction of ERK-kinase signalling triggers morphotype-specific killing of Candida albicans filaments by human neutrophils. Cell Microbiol. 2008;10:807–20.
  47. Ermert D, Niemiec MJ, Rohm M, Glenthoj A, Borregaard N, Urban CF. Candida albicans escapes from mouse neutrophils. J Leukoc Biol. 2013;94:223–36.
  48. Lionakis MS, Netea MG. Candida and host determinants of susceptibility to invasive candidiasis. PLoS Pathog. 2013;9:e1003079.
  49. Ngo LY, Kasahara S, Kumasaka DK, Knoblaugh SE, Jhingran A, Hohl TM. Inflammatory monocytes mediate early and organ-specific innate defense during systemic candidiasis. J Infect Dis. 2014;209:109–19.
  50. Espinosa V, Jhingran A, Dutta O, Kasahara S, Donnelly R, Du P, et al. Inflammatory monocytes orchestrate innate antifungal immunity in the lung. PLoS Pathog. 2014;10:e1003940.
  51. Break TJ, Jaeger M, Solis NV, Filler SG, Rodriguez CA, Lim JK, et al. CX3CR1 is dispensable for control of mucosal Candida albicans infections in mice and humans. Infect Immun. 2015;83:958-965.
  52. Park SJ, Burdick MD, Brix WK, Stoler MH, Askew DS, Strieter RM, et al. Neutropenia enhances lung dendritic cell recruitment in response to Aspergillus via a cytokine-to-chemokine amplification loop. J Immunol. 2010;185:6190–7.
  53. Morrison BE, Park SJ, Mooney JM, Mehrad B. Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis. J Clin Invest. 2003;112:1862–70.
  54. Bar E, Whitney PG, Moor K, Reis e Sousa C, LeibundGut-Landmann S. IL-17 regulates systemic fungal immunity by controlling the functional competence of NK cells. Immunity. 2014;40:117–27.
  55. Benedetto N, Sabatini P, Sellitto C, Romano Carratelli C. Interleukin-2 and increased natural killer activity in mice experimentally infected with Aspergillus niger. Microbiologica. 1988;11:339–45.
  56. Park SJ, Hughes MA, Burdick M, Strieter RM, Mehrad B. Early NK cell-derived IFN-{gamma} is essential to host defense in neutropenic invasive aspergillosis. J Immunol. 2009;182:4306–12.
  57. Stuehler C, Kuenzli E, Jaeger VK, Baettig V, Ferracin F, Rajacic Z, et al. Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis. J Infect Dis. 2015;212:959–67.
  58. Schmidt S, Tramsen L, Hanisch M, Latge JP, Huenecke S, Koehl U, et al. Human natural killer cells exhibit direct activity against Aspergillus fumigatus hyphae, but not against resting conidia. J Infect Dis. 2011;203:430–5.
  59. Bouzani M, Ok M, McCormick A, Ebel F, Kurzai O, Morton CO, et al. Human NK cells display important antifungal activity against Aspergillus fumigatus, which is directly mediated by IFN-gamma release. J Immunol. 2011;187:1369–76.
  60. Lünemann A, Lunemann JD, Munz C. Regulatory NK. Cell Functions in Inflammation and Autoimmunity. Mol Med. 2009.
  61. Bhatnagar N, Hong HS, Krishnaswamy JK, Haghikia A, Behrens GM, Schmidt RE, et al. Cytokine-activated NK cells inhibit PMN apoptosis and preserve their functional capacity. Blood. 2010;116:1308–16.
  62. Costantini C, Micheletti A, Calzetti F, Perbellini O, Pizzolo G, Cassatella MA. Neutrophil activation and survival are modulated by interaction with NK cells. Int Immunol. 2010;22:827–38.
  63. Voigt J, Hunniger K, Bouzani M, Jacobsen ID, Barz D, Hube B, et al. Human natural killer cells acting as phagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity. J Infect Dis. 2014;209:616–26.
  64. Li SS, Kyei SK, Timm-McCann M, Ogbomo H, Jones GJ, Shi M, et al. The NK receptor NKp30 mediates direct fungal recognition and killing and is diminished in NK cells from HIV-infected patients. Cell Host Microbe. 2013;14:387–97.
  65. Michel T, Hentges F, Zimmer J. Consequences of the crosstalk between monocytes/macrophages and natural killer cells. Front Immunol. 2012;3:403.
  66. Newman KC, Riley EM. Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens. Nat Rev Immunol. 2007;7:279–91.
  67. Whitney PG, Bar E, Osorio F, Rogers NC, Schraml BU, Deddouche S, et al. Syk signaling in dendritic cells orchestrates innate resistance to systemic fungal infection. PLoS Pathog. 2014,10:e1004276.
  68. Lünemann A, Vanoaica LD, Azzi T, Nadal D, Munz C. A distinct subpopulation of human NK cells restricts B cell transformation by EBV. Journal of Immunology. 2013;191:4989–95.
  69. Hohl TM, Rivera A, Lipuma L, Gallegos A, Shi C, Mack M, et al. Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection. Cell Host Microbe. 2009;6:470–81.
  70. LeibundGut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV, et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007;8:630–8.
  71. Rivera A, Ro G, Van Epps HL, Simpson T, Leiner I, Sant'Angelo DB, et al. Innate immune activation and CD4+ T cell priming during respiratory fungal infection. Immunity. 2006,25:665–75.
  72. Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, et al. Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta. Nature. 2012;484:514–18.
  73. Marukutira T, Huprikar S, Azie N, Quan SP, Meier-Kriesche HU, Horn DL. Clinical characteristics and outcomes in 303 HIV-infected patients with invasive fungal infections: data from the Prospective Antifungal Therapy Alliance registry, a multicenter, observational study. HIV AIDS (Auckl). 2014;6:39–47.
  74. Nagai H, Guo J, Choi H, Kurup V. Interferon-gamma and tumor necrosis factor-alpha protect mice from invasive aspergillosis. J Infect Dis. 1995;172:1554–60.
  75. Roilides E, Dimitriadou-Georgiadou A, Sein T, Kadiltsoglou I, Walsh TJ. Tumor necrosis factor alpha enhances antifungal activities of polymorphonuclear and mononuclear phagocytes against Aspergillus fumigatus. Infect Immun. 1998;66:5999–6003.
  76. Sparber F, LeibundGut-Landmann S. Interleukin 17-Mediated Host Defense against Candida albicans. Pathogens. 2015;4:606–19.
  77. Gladiator A, Wangler N, Trautwein-Weidner K, LeibundGut-Landmann S. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J Immunol. 2013;190:521-525.
  78. Carvalho A, De Luca A, Bozza S, Cunha C, D'Angelo C, Moretti S, et al. TLR3 essentially promotes protective class I-restricted memory CD8(+) T-cell responses to Aspergillus fumigatus in hematopoietic transplanted patients. Blood. 2012;119:967–77.
  79. Stuehler C, Nowakowska J, Bernardini C, Topp MS, Battegay M, Passweg J, et al. Multispecific Aspergillus T cells selected by CD137 or CD154 induce protective immune responses against the most relevant mold infections. J Infect Dis. 2015;211:1251–61.
  80. Stuehler C, Bernardini C, Elzi L, Stoeckle M, Zimmerli S, Furrer H, et al. Immune recovery in HIV-infected patients after candida esophagitis is impaired despite long-term antiretroviral therapy. AIDS. 2016;30(12):1923–33.
  81. Wojtowicz A, Bochud PY. Host genetics of invasive Aspergillus and Candida infections. Semin Immunopathol. 2015;37:173–86.
  82. Bochud PY, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008;359:1766–77.
  83. Van der Graaf CA, Netea MG, Morre SA, Den Heijer M, Verweij PE, Van der Meer JW, et al. Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw. 2006;17:29–34.
  84. Richardson ED, Malloy PF, Grace J. Othello syndrome secondary to right cerebrovascular infarction. J Geriatr Psychiatry Neurol. 1991;4:160–5.
  85. Kesh S, Mensah NY, Peterlongo P, Jaffe D, Hsu K, van den Brink MB, et al. TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation. Ann N Y Acad Sci. 2005;1062:95–103.
  86. Koldehoff M, Beelen DW, Elmaagacli AH. Increased susceptibility for aspergillosis and post-transplant immune deficiency in patients with gene variants of TLR4 after stem cell transplantation. Transpl Infect Dis. 2013;15:533–9.
  87. Cunha C, Di Ianni M, Bozza S, Giovannini G, Zagarella S, Zelante T, et al. Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood. 2010;116:5394–402.
  88. Ferwerda B, Ferwerda G, Plantinga TS, Willment JA, van Spriel AB, Venselaar H, et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med. 2009;361:1760–7.
  89. Plantinga TS, van der Velden WJ, Ferwerda B, van Spriel AB, Adema G, Feuth T, et al. Early stop polymorphism in human DECTIN-1 is associated with increased candida colonization in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2009;49:724–32.
  90. Wojtowicz A, Gresnigt MS, Lecompte T, Bibert S, Manuel O, Joosten LA, et al. IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation. J Infect Dis. 2015;211:1646–57.
  91. Sainz J, Perez E, Gomez-Lopera S, Jurado M. IL1 gene cluster polymorphisms and its haplotypes may predict the risk to develop invasive pulmonary aspergillosis and modulate C-reactive protein level. J Clin Immunol. 2008;28:473–85.
  92. Lionakis MS, Swamydas M, Fischer BG, Plantinga TS, Johnson MD, Jaeger M, et al. CX3CR1-dependent renal macrophage survival promotes Candida control and host survival. J Clin Invest. 2013,123:5035–51.
  93. Swamydas M, Gao JL, Break TJ, Johnson MD, Jaeger M, Rodriguez CA, et al. CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival. Sci Transl Med. 2016;8:322ra310.
  94. Cunha C, Aversa F, Lacerda JF, Busca A, Kurzai O, Grube M, et al. Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med. 2014;370:421–32.
  95. Wojtowicz A, Lecompte TD, Bibert S, Manuel O, Rueger S, Berger C, et al. PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant. Clin Infect Dis. 2015;61:619–22.
  96. Lo Giudice P, Campo S, De Santis R, Salvatori G. Effect of PTX3 and voriconazole combination in a rat model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2012;56:6400–2.
  97. Estcourt LJ, Stanworth S, Doree C, Blanco P, Hopewell S, Trivella M, et al. Granulocyte transfusions for preventing infections in people with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. 2015;CD005341.
  98. Armstrong-James D, Harrison TS. Immunotherapy for fungal infections. Curr Opin Microbiol. 2012;15:434–9.
  99. Wan L, Zhang Y, Lai Y, Jiang M, Song Y, Zhou J, et al. Effect of Granulocyte-Macrophage Colony-Stimulating Factor on Prevention and Treatment of Invasive Fungal Disease in Recipients of Allogeneic Stem-Cell Transplantation: A Prospective Multicenter Randomized Phase IV Trial. J Clin Oncol. 2015,33:3999–4006.
  100. Lambourne J, Agranoff D, Herbrecht R, Troke PF, Buchbinder A, Willis F, et al. Association of mannose-binding lectin deficiency with acute invasive aspergillosis in immunocompromised patients. Clin Infect Dis. 2009;49:1486–491.
  101. Knorr DA, Bachanova V, Verneris MR, Miller JS. Clinical utility of natural killer cells in cancer therapy and transplantation. Semin Immunol. 2014;26:161–72.
  102. Locatelli F, Moretta F, Brescia L, Merli P. Natural killer cells in the treatment of high-risk acute leukaemia. Semin Immunol. 2014;26:173–9.
  103. Peggs KS, Thomson K, Samuel E, Dyer G, Armoogum J, Chakraverty R, et al. Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation. Clin Infect Dis. 2011,52:49–57.
  104. Papadopoulou A, Gerdemann U, Katari UL, Tzannou I, Liu H, Martinez C, et al. Activity of Broad-Spectrum T Cells as Treatment for AdV, EBV, CMV, BKV, and HHV6 Infections after HSCT. Sci Transl Med. 2014;6:242ra283.
  105. Haque T, Wilkie GM, Taylor C, Amlot PL, Murad P, Iley A, et al. Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet. 2002;360:436–42.
  106. Perruccio K, Tosti A, Burchielli E, Topini F, Ruggeri L, Carotti A, et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood. 2005;106:4397–406.
  107. Jolink H, Hagedoorn RS, Lagendijk EL, Drijfhout JW, van Dissel JT, Falkenburg JH, et al. Induction of A. fumigatus-specific CD4-positive T-cells in patients recovering from invasive aspergillosis. Haematologica. 2014;99(7):1255–63.
  108. Potenza L, Vallerini D, Barozzi P, Riva G, Forghieri F, Beauvais A, et al. Characterization of specific immune responses to different Aspergillus antigens during the course of invasive Aspergillosis in hematologic patients. PLoS One. 2013;8:e74326.
  109. Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634–53.
  110. Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect. 2011;17:1859–67.
  111. Stuehler C, Khanna N, Bozza S, Zelante T, Moretti S, Kruhm M, et al. Cross-protective TH1 immunity against Aspergillus fumigatus and Candida albicans. Blood. 2011;117:5881–91.
  112. Deo SS, Gottlieb DJ. Adoptive T-cell therapy for fungal infections in haematology patients. Clin Transl Immunology. 2015;4:e40.
  113. Feuchtinger T, Matthes-Martin S, Richard C, Lion T, Fuhrer M, Hamprecht K, et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol. 2006;134:64–76.
  114. Khanna N, Stuehler C, Conrad B, Lurati S, Krappmann S, Einsele H, et al. Generation of a multipathogen-specific T-cell product for adoptive immunotherapy based on activation-dependent expression of CD154. Blood. 2011;118:1121–31.
  115. Jolink H, Meijssen IC, Hagedoorn RS, Arentshorst M, Drijfhout JW, Mulder A, et al. Characterization of the T-cell-mediated immune response against the Aspergillus fumigatus proteins Crf1 and catalase 1 in healthy individuals. J Infect Dis. 2013;208:847–56.
  116. Tramsen L, Koehl U, Tonn T, Latge JP, Schuster FR, Borkhardt A, et al. Clinical-scale generation of human anti-Aspergillus T cells for adoptive immunotherapy. Bone Marrow Transplant. 2009;43:13–9.
  117. Tramsen L, Schmidt S, Boenig H, Latge JP, Lass-Florl C, Roeger F, et al. Clinical-scale generation of multi-specific anti-fungal T cells targeting Candida, Aspergillus and mucormycetes. Cytotherapy. 2013;15:344–51.
  118. Beck O, Topp MS, Koehl U, Roilides E, Simitsopoulou M, Hanisch M, et al. Generation of highly purified and functionally active human TH1 cells against Aspergillus fumigatus. Blood. 2006;107:2562–9.
  119. Kumaresan PR, Manuri PR, Albert ND, Maiti S, Singh H, Mi T, et al. Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A. 2014;111:10660–5.
  120. Bozza S, Clavaud C, Giovannini G, Fontaine T, Beauvais A, Sarfati J, et al. Immune sensing of Aspergillus fumigatus proteins, glycolipids, and polysaccharides and the impact on Th immunity and vaccination. J Immunol. 2009;183:2407–14.
  121. Bacher P, Kniemeyer O, Teutschbein J, Thon M, Vodisch M, Wartenberg D, et al. Identification of Immunogenic Antigens from Aspergillus fumigatus by Direct Multiparameter Characterization of Specific Conventional and Regulatory CD4+ T Cells. J Immunol. 2014;193(7):3332–43.
  122. Chaudhary N, Staab JF, Marr KA. Healthy human T-Cell Responses to Aspergillus fumigatus antigens. PLoS One. 2010;5:e9036.
  123. Potenza L, Vallerini D, Barozzi P, Riva G, Forghieri F, Beauvais A, et al. Characterization of specific immune responses to different Aspergillus antigens during the course of invasive Aspergillosis in hematologic patients. PLoS One. 2013;8:e74326.
  124. Ramadan G, Davies B, Kurup VP, Keever-Taylor CA. Generation of cytotoxic T cell responses directed to human leucocyte antigen Class I restricted epitopes from the Aspergillus f16 allergen. Clin Exp Immunol. 2005;140:81–91.
  125. Ramadan G, Davies B, Kurup VP, Keever-Taylor CA. Generation of Th1 T cell responses directed to a HLA Class II restricted epitope from the Aspergillus f16 allergen. Clin Exp Immunol. 2005;139:257–67.
  126. Diaz-Arevalo D, Bagramyan K, Hong TB, Ito JI, Kalkum M. CD4+ T cells mediate the protective effect of the recombinant Asp f3-based anti-aspergillosis vaccine. Infect Immun. 2011;79:2257–66.
  127. Diaz-Arevalo D, Ito JI, Kalkum M. Protective Effector Cells of the Recombinant Asp f3 Anti-Aspergillosis Vaccine. Front Microbiol. 2012;3:299.
  128. Hebart H, Bollinger C, Fisch P, Sarfati J, Meisner C, Baur M, et al. Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies. Blood. 2002;100:4521–8.

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