Skip to main navigation menu Skip to main content Skip to site footer

Systematic Review

Vol. 10 No. 1 (2007)

Protective Immunity Against Cryptococcus Neoformans Infection

  • Joel Schop
DOI
https://doi.org/10.26443/mjm.v10i1.467
Submitted
November 1, 2020
Published
2020-12-01

Abstract

Cryptococcus neoformans, the etiological agent of cryptococcosis, is an occasional opportunistic fungal pathogen of immune competent individuals. However, it is a relatively frequent cause of life-threatening meningoencephalitis and pulmonary infections in immunosuppressed hosts and is a leading mycological cause of morbidity and mortality among patients with AIDS in most parts of the world. The lack of an effective fungicidal regimen and the development of antifungal resistant strains suggest that continued investigation is necessary to devise immunotherapeutic strategies, drug targets and/or vaccines to combat C. neoformans infections. Until recently, cryptococcal virulence factors such as its polysaccharide capsule, macrophage parasitism, and its ability to induce an ineffective antibody mediated immune (AMI) response along with a non-protective type II (Th2) cell-mediated immune response have thwarted efforts to induce complete protective immunity against a lethal cryptococcal strain in murine models. The presence of C. neoformans antibodies in adult human serum suggests that immune competent individuals have difficulty resolving an early cryptococcal infection allowing for the establishment of a subclinical chronic infection. Recent studies have shown that pro-inflammatory cytokines, specifically interferon-g (IFN-g), associated with type I (Th1) cell-mediated immunity can successfully drive cell-mediated immune (CMI) responses to produce protective immunity to a second experimental C. neoformans infection in mice. This review will evaluate the intricacies of the host-cryptococcal interaction and discuss recent developments in C.neoformans research and the potential for human vaccines and/or drug therapies.

References

  1. Bayer A, Choi C, Tillman D, et al. Fungal arthritis: V. Cryptococcal and Histoplasmal Arthritis. Semin Arth Rheum 1980; 9:218-227.
  2. Boden W, Fisher A, Medeiros A, et al. Bioprosthetic Endocarditis due to Cryptococcus Neoformans. J Cardiovasc Surg 1983; 24:164-166.
  3. Chuck SL, Sande MA. Infections with Cryptococcus Neoformans in the Acquired Immunodeficiency Syndrome. N Engl J Med 1989; 321:794-9.
  4. Kovacs, J. A., A. A. Kovacs, M. Polis, et al. Cryptococcosis in the Acquired Immunodeficiency Syndrome. Ann Intern Med 1985; 103:533-538.
  5. Powderly, WG. Cryptococcal meningitis and AIDS. Clin Infect Dis 1993; 17:837-842.
  6. Schutte C, Van der Meyden C, Magazi D. The impact of HIV on meningitis as seen at a South African Academic Hospital (1994 to 1998). Infection 2000: 28(1):3-7.
  7. Currie BP, Casadevall A. Estimation of the prevalence of cryptococcal infection among HIV infected individuals in New York City. Clin Infect Dis 1994; 19:1029-1033.
  8. Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in Human Immunodeficiency Virus negative Patients in the Era of Effective Azole Therapy. Clin Infect Dis 2001; 33: 690-699.
  9. Ecevit I, Clancy C, Schmalfuss I, et al. The Poor Prognosis of Central Nervous System Cryptococcosis among Nonimmunosuppressed Patients: a Call for Better Disease Recognition and Evaluation of Adjuncts to Antifungal Therapy. Clin Infect Dis 2006; 42: 1443-1447.
  10. Aberg JA, Price RW, Heeren DM, Bredt B. A Pilot Study of the Discontinuation of Antifungal Therapy for Disseminated Cryptococcal Disease in the Patients with Acquired Immunodeficiency Syndrome, following Immunologic Response to Antiretroviral tTerapy. J Infect Dis 2002; 185:1179-82.
  11. Shelburne SA, Darcourt III, White AC, Jr, et al. The Role of Immune Reconstitution Inflammatory Syndrome in AIDS-Rlated Cryptococcus Neoformans Disease in the Era of Highly Active Antiretroviral Therapy. Clin Infect Dis 2005; 40:1049-1052.
  12. Kwon-Chung K, Varma A. Do Major Species Concepts Support One, Two or More Species within Cryptococcus Neoformans? FEMS Yeast Res 2006; 6:574-587.
  13. Mitchell TG, Perfect JR. Cryptococcosis in the Era of AIDS-100 Years after the Discovery of C. neoformans. Clin Microbiol Rev 1995; 8:515-48.
  14. Viviani M, Cogliati M, Esposto M, et al. Molecular analysis of 311 Cryptococcus Neoformans Isolates from a 30-month ECMM Survey of Cryptococcosis in Europe. FEMS Yeast Res 2006; 6(4):614-9.
  15. Wang Y, Casadevall A. Susceptibility of Melanized and Nonmelanized Cryptococcus Neoformans to Nitrogen- and Oxygen-derived Oxidants. Infect Immun 1994; 62(7):3004-7.
  16. Jacobson E, Tinnell S. Antioxidant Function of Fungal Melanin. J Bacteriol 1993; 175(21):7102-4.
  17. Wang Y, Aisen P, Casadevall A. Cryptococcus Neoformans Melanin and Virulence: Mechanism of Action. Infect Immun 1995; 63(8):3131-6.
  18. Jacobson E, Jenkins N, Todd J. Relationship between Superoxide Dismutase and Melanin in a Pathogenic Fungus. Infect Immun 1994; 62(9):4085-6.
  19. Cox G, Harrison T, McDade H, et al. Superoxide Dismutase Influences the Virulence of Cryptococcus Neoformans by Affecting Growth within Macrophages. Infect Immun 2003; 71(1):173-80.
  20. Perfect J, Wong B, Chang Y, et al. Cryptococcus Neoformans: Virulence and Host Defences. Med Mycol 1998; 36(1):79-86.
  21. Wormley FL, Heinrich G, Miller J, et al. Identification and Characterization of an SKN7 Homologue in Cryptococcus Neoformans. Infect Immun 2005; 73(8):5022-30.
  22. Kozel TR, Gulley WF, Cazin JJ. Immune Response to Cryptococcus Neoformans Soluble Polysaccharide: Immunological Unresponsiveness. Infect Immun 1977; 18:701-707.
  23. Sundstrom JB, Cherniak R. A Glucuronoxylomannan of Cryptococcus Neoformans Serotype A is a Type 2 T-cell- independent antigen. Infect Immun 1992; 60:4080-4087.
  24. Murphy JW, Cozad GC. Immunological Unresponsiveness Induced by Cryptococcal Polysaccharide Assayed by the Hemolytic Plaque Technique. Infect Immun 1972; 5:896-901.
  25. Goldman DL, Khine H, Abadi J, et al. Serologic Evidence for Cryptococcus Infection in the Early Childhood. Pediatrics 2001;107:E66
  26. Abadi J, Pirofski L. Antibodies Reactive with the Cryptococcal Capsular Polysaccharide Glucuronoxylomannan are Present in Ssera from Children with and without HIV Infection. J Infect Dis 1999; 180:915-919.
  27. Kuttin ES, Feldman M, Nyska A, et al. Cryptococcosis of the Nasopharynx in Mice and Rats. Mycopathologia 1988; 101:99-104.
  28. Kuhn, LR. Growth and Viability of Cryptococcus Hominis at Mouse and Rabbit Body Temperatures. Proc Soc Exp Biol Med 1939; 41:573-574.
  29. Casadevall A and Perfect JR. In: editors name. Cryptococcus Neoformans. Washington, DC: ASM Press; 1998: 177-181.
  30. Chen S. Sorrel T, Nimmo G, et al. Epidiology and Host- and Variety-dependent Characteristics of Infection due to Cryptococcus Neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis 2000; 31:499-508.
  31. Kozel, TR. Opsonization and Phygocytosis of Cryptococcus Neoformans. Arh Med Res 1993; 9:34-46.
  32. Keller RG, Pfrommer GS, Kozel TR. Occurrences, Specificity, and Functions of Ubiquitous Antibodies in Human Serum that are Reactive with the Cryptococcus Neoformans Cell Wall. Infect Immun 1994; 62:215-220.
  33. Houpt DC, Pfrommer GST, Young BJ, et al. Occurrences, Immunoglobulin Classes, and Biological Activities of Antibodies in Normal Human Sserum that are Reactive to Cryptococcus Neoformans Glucuronoxylomannan. Infect Immun 1994; 82:3857-3864.
  34. Kozel TR, Wilson MA, Pfrommer GS, et al. Activation and Binding of Opsonic Fragments of C3 on Encapsulated and Nonencapsulated Cryptococcus Neoformans by Using an Alternative Complement Pathway Reconstituted from Six Isolated Patients. Infect Immun 1989; 57:1922-1927.
  35. Miller MF, Mitchell TG. Killing of Cryptococcus Neoformans Strains by Human Neutrophils and Monocytes. Infect Immun 1991; 59:24-28.
  36. Marr K, Jones G, Mody C. Contemplating the Murine Test Tube: Lessons from Natural Killer Cells and Cryptococcus Neoformans. FEMS Yeast Res 2006; 6(4):543-57.
  37. Salkowski CA, Balish E. Role of Natural Killer Cells in Resistance to Systemic Cryptococcosis. J Leukocyte Biol 1991; 50:151-159.
  38. Ganz T, Selsted ME, Szklarek D, et al. Defensins, Natural Peptide Antibiotics of the Human Neutrophils. J Clin Invest 1972; 76:1427-1435.
  39. Diamond RD, Root RK, Bennett JE. Factors Influencing Killing of Cryptococcus Neoformans by Human Leukocytes in Vitro. J Infect Dis 1972; 125:367-376.
  40. Hiemstra PS, Eisenhauer PB, Harwig LS, et al. Antimicrobial Proteins of the Murine Macrophages. Infect Immun 1993; 61:3038-3046.
  41. Brummer E, Stevens DA. Anticryptococcal Activity of Macrophages: Role of Mouse Strain, C5, Contact, Phagocytosis an L-arginine. Cell Immunol 1994; 157:1-10.
  42. Flesch IEA, Schwamberger G, Kaufman SHE. Fungicidal Activity of IFN-? Activated Macrophages. J Immunol 1989; 142:3219-3224.
  43. Collins HL, Bancroft GJ. Cytokine Enhancement of Complement-dependent Phagocytosis by Macrophages: Synergy of Tumor Necrosis Factor-alpha and Granulocyte-Macrophage Colony Stimulation Factor for Phagocytosis of Cryptococcus Neoformans. Eur J Immunol 1992; 22:1447-1454.
  44. Diamond RD, Bennett JE. Growth of Cryptococcus Neoformans within Human Macrophages in Vitro. Infect Immun 1973; 7:231-236.
  45. Feldmesser M, Kress Y, Novikoff P et al. Cryptococcus Neoformans is a Facultative Intracellular Pathogen in Murine Pulmonary Infection. Infect Immun 2000; 68:4225-4237.
  46. Feldmesser M, Tucker S, and Casadevall A. Intracellular Parasitism of Mophages by Cryptococcus Neoformans. Trends Microbiol 2001; 6:273-8.
  47. Vecchiarelli A. Immunoregulation by Capsular Components of Cryptococcus Neoformans. Med Mycol 2000; 38:407-417.
  48. Devi SJN. Preclinical Efficacy of a Glucuronoxylomannan-Tetanus Toxoid Conjugate Vaccine of Cryptococcus Neoformans in a Murine Model. Vaccine 1996; 14:841-842.
  49. Devi SJ, Schneerson R, Egan W, et al. Cryptococcus Neoformans Serotype A Glucuronoxylomannan-protein Conjugate Vaccines: Synthesis, Characterization, and Immunogenicity. Infect Immun. 1991; 59(10):3700-7.
  50. Rivera J, Mukherjee J, Weiss LM, et al. Antibody Efficacy in Murine Pulmonary Cryptococcus Neoformans Infection: a Role for Nitric Oxide. J Immunol 2002; 168:3419-3427.
  51. Williamson PR, Bennett JE, Polis MA, et al. Immunogenicity and Safety of a Conjugate Glucuronoxylomannan-tetanus Conjugate Vaccine in Volunteers. Clin Infect Dis 1993; 17:540.
  52. Lim TS, Murphy JW. Transfer of Immunity to Cryptococcosis by T-enriched Splenic Lymphocytes from Cryptococcus Neoformans-sensitized Mice. Infect Immun 1980; 30:5-11.
  53. Wormley FL, Perfect JR, Steele C, et al. Protection Against Cryptococcosis using Murine Interferon-gamma Producing Cryptococcus Neoformans Strain. Cryptococcus & Cryptococcosis Tri-annual Meeting, June 2005.
  54. Cauley LK, Murphy JW. Response of Congenitally Athymic (nude) and Phenotypically Normal Mice to Cryptococcus Neoformans Infection. Infect Immun 1979; 23:644-651.
  55. Salkowski CA, Balish E. Susceptibility of Congenitally Immunodeficiant Mice to an Encapsulated Strain of Cryptococcus Neoformans. Can J Microbiol 1991; 37:834-839.
  56. Salkowski CA, Balish E. Inflammatory Responses to Cryptococcosis in Congenitally Athymic Mice. J Leukocyte Biol 1991; 49:533-541.
  57. Graybill JR, Ahrens J, Nealon T, Paque R. Pulmonary Cryptococcosis in the Rat. Am Rev Respir Dis 1983; 127:636-640.
  58. Wormley FL, Cox GM, Perfect JR. Evaluation of Host Immune Responses to Pulmonary Cryptococcosis using a Temperature-Sensitive Cryptococcus Neoformans Calcineurin A Mutant Strain. Microb Pathog2005; 38:113-123.
  59. Odom A, Muir S, Lim E, et al. Calcineurin is Required for Virulence of Cryptococcus Neoformans. EMBO J 1997; 16:2579-2589.
  60. Hernandez Y, Arora S, Erb-Downward JR, et al. Distinct Roles for IL-4 and IL-10 in Regulating TH2 Immunity during Allergic Bronchopulmonary Mycosis. J Immunol 2005; 174(2):1027-36.
  61. Furukawa K, Kobayashi M, Sasaki H, et al. Cryptococcal Encephalitis in Thermally Injured Mice is Accelerated by Type 2 T-cell Responses. Crit Care Med 2002; 30(7):1419-24.
  62. Murphy JW, Schafer F, Casadevall A, et al. Antigen-induced Protective and Nonprotective Cell-mediated Immune Components against Cryptococcus Neoformans. Infect Immun 1998; 66:2632-2639.
  63. Mandel MA, Grace GC, Orsborn KI, et al. The Cryptococcus Neoformans Gene DHA1 Encodes an Antigen that Elicits a Delayed-type Hpersensitivity Reaction in Immune Mice. Infect Immun 2000; 68:6196-6201.
  64. Biondo C, Beninati C, Delfino D, et al. Identification and Cloning of a Cryptococcal Deacetylase that Produces Protective Immune Responses. Infect Immun 2002; 70(5):2383-91.
  65. Levitz SM, Nong S, Mnasour MK, et al. Molecular Characterization of a Mannoprotien with Homology to Chitin Deacetylases that Stimulates T cell Responses to Cryptococcus Neoformans. Proc Natl Acad Sci USA 2001; 98:10422-10427.
  66. Huang C, Nong SH, Mansour MK, et al. Purification and Characterization of a Second Immunoreactive Mannoproteins from Cryptococcus Neoformans that Stimulates T-cell Responses. Infect Immun 2002; 70:5485-5493.
  67. Biondo C, Messina L, Bombaci M, et al. Characterization of Two Novel Cryptococcal Mannoproteins Recognized by Immune Sera. Infect Immun 2005; 73(11):7348-55.
  68. Sallusto F, Cella M, Danieli C, et al. Dendritic Cells use Macropinocytosis and the Mannose Receptor to Concentrate Macromolecules in the Major Histocompatibility Complex Class II Compartment: Downregulation by Cytokines and Bacterial Products. J Exp Med 1995; 182:389-400.
  69. Levitz SM, Specht CA. The Molecular Basis for the Immunogenicity of Cryptococcus Neoformans Mannoproteins. FEMS Yeast Res 2006; 6(4):513-24.
  70. Pitzurra L, Cherniak R, Giammarioli M, et al. Early Induction of Interleukin-12 by Human Monocytes Exposed to Cryptococcus Neoformans Mannoproteins. Infect Immun 2000; 68(2):558-63.
  71. Pietrella D, Cherniak R, Strappini C, et al. Role ofMannoprotein in Induction and Regulation of Immunity to Cryptococcus Neoformans. Infect Immun 2001; 69(5):2808-14.
  72. Pietrella D, Mazzolla R, Lupo P, et al. Mannoprotein from Cryptococcus Neoformans Promotes T-helper Type 1 Anticandidal Responses in Mice. Infect Immun 2002; 70(12):6621-7.
  73. Mansour MK, Schlesinger LS, Levitz SM. Optimal T cell Responses to Cryptococcus Neoformans Mannoproteins are Dependent on Recognition of Conjugated Carbohydrates by Mannose Receptors. J Immunol 2002; 168:2872-2879.
  74. Vecchiarelli A, Retini C, Monari C, et al. Purified Capsular Polysaccharide of Cryptococcus Neoformans Induces Interleukin-10 Secretion by Human Monocytes. Infect Immun 1996; 64:2846-9.
  75. Mansour MK, Yauch LE, Rottman JB, et al. Protective Efficacy of Antigenic Fractions in Mouse Models of Cryptococcosis. Infect Immun 2004; 72(3):1746-54.

Downloads

Download data is not yet available.