Histoplasma capsulatum Chaperonin 60: A Novel Adhesin and Vaccine Candidate

  • Joshua Daniel Nosanchuk
  • Allan Jefferson Guimarães
Part of the Heat Shock Proteins book series (HESP, volume 7)


HSP60 has a key role in immunoregulation and the abundance of HSP60 proteins in mammalian and microbial cells impacts diverse biological functions in both. Therefore, it may be essential for innate immune cells to distinguish HSP60 proteins by their endogenous or infectious origin. Histoplasma capsulatum (Hc) is able to express an Hsp60 on its surface that facilitates engagement with macrophages through complement 3 receptors (CR3) and leads to phagocytosis of the fungus where the pathogen survives within phagosomes. HcHsp60 plays important metabolic roles related to the fungal adaptation to temperature and oxidative stress conditions. Hc is also able to secrete this chaperone, which could play important roles in modulation of the antifungal immunological responses. Vaccination with recombinant HcHsp60 has conferred protection in mouse models against intravenous and pulmonary infections by Hc. Passive immunization using monoclonal antibodies to HcHsp60 has provided excellent results against Hc in mouse models, mainly by activating the antifungal functions of macrophages and inducing a Th-1 type immunoresponse. As Hsp60 is a common fungal antigen, passive immunization with Hsp60 mAbs has been evaluated against distinct fungal pathogens, including coupling the antibody with radionuclides (radioimmunotherapy) in order to increase the antifungal potential of these mAbs. In this chapter, we detail the research progresses on Hsp60 of Hc with particular focus on its characterization as an adhesin and utilization in vaccination and passive immunization.


Invasive Fungal Infection Heat Shock Response Passive Immunization Histoplasma Capsulatum Yeast Phase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ajello L (1971) Coccidioidomycosis and histoplasmosis. A review of their epidemiology and geographical distribution. Mycopathol Mycol Appl 45:221–230PubMedCrossRefGoogle Scholar
  2. Allendoerfer R, Biovin GP, Deepe GS Jr (1997) Modulation of immune responses in murine pulmonary histoplasmosis. J Infect Dis 175:905–914PubMedCrossRefGoogle Scholar
  3. Allendorfer R, Brunner GD, Deepe GS Jr (1999) Complex requirements for nascent and memory immunity in pulmonary histoplasmosis. J Immunol 162:7389–7396PubMedGoogle Scholar
  4. Alteras I (1966) First Romanian isolation of Histoplasma capsulatum from the soil. Dermatol Int 5:69–71PubMedCrossRefGoogle Scholar
  5. Barreto A, Gonzalez JM, Kabingu E, Asea A, Fiorentino S (2003) Stress-induced release of HSC70 from human tumors. Cell Immunol 222:97–104PubMedCrossRefGoogle Scholar
  6. Borelli D (1970) Prevalence of systemic mycosis in Latin America. In: Proceedings of international symposium on mycoses. Scientific Publication, PAHO, Washington, DC, 205Google Scholar
  7. Borgia G, Tallarino A, Crowell J, Lambiase A, Cicciarello S, Reynaud L, Nasti G, Piazza M (1990) The effect of temperature on the ultrastructure of Histoplasma capsulatum during the mycelium-yeast transition. Mycoses 33:405–410PubMedGoogle Scholar
  8. Bradsher RW (1996) Histoplasmosis and blastomycosis. Clin Infect Dis 22(Suppl 2):S102–S111PubMedCrossRefGoogle Scholar
  9. Bryan RA, Guimaraes AJ, Hopcraft S, Jiang Z, Bonilla K, Morgenstern A, Bruchertseifer F, Del Poeta M, Torosantucci A, Cassone A, Nosanchuk JD, Casadevall A, Dadachova E (2012) Toward developing a universal treatment for fungal disease using radioimmunotherapy targeting common fungal antigens. Mycopathologia 173:463–471PubMedCrossRefGoogle Scholar
  10. Burnie JP, Carter TL, Hodgetts SJ, Matthews RC (2006) Fungal heat-shock proteins in human disease. FEMS Microbiol Rev 30:53–88PubMedCrossRefGoogle Scholar
  11. Cain JA, Deepe GS Jr (1998) Evolution of the primary immune response to Histoplasma capsulatum in murine lung. Infect Immun 66:1473–1481PubMedGoogle Scholar
  12. Cano MV, Hajjeh RA (2001) The epidemiology of histoplasmosis: a review. Semin Respir Infect 16:109–118PubMedCrossRefGoogle Scholar
  13. Carratu L, Franceschelli S, Pardini CL, Kobayashi GS, Horvath I, Vigh L, Maresca B (1996) Membrane lipid perturbation modifies the set point of the temperature of heat shock response in yeast. Proc Natl Acad Sci U S A 93:3870–3875PubMedCrossRefGoogle Scholar
  14. Caruso M, Sacco M, Medoff G, Maresca B (1987) Heat shock 70 gene is differentially expressed in Histoplasma capsulatum strains with different levels of thermotolerance and pathogenicity. Mol Microbiol 1:151–158PubMedCrossRefGoogle Scholar
  15. Couto MA, Liu L, Lehrer RI, Ganz T (1994) Inhibition of intracellular Histoplasma capsulatum replication by murine macrophages that produce human defensin. Infect Immun 62:2375–2378PubMedGoogle Scholar
  16. Csillag A, Wermer T (1956) Histoplasmosis. Orv Hetil 97:964–967PubMedGoogle Scholar
  17. Davies EL, Bacelar MM, Marshall MJ, Johnson E, Wardle TD, Andrew SM, Williams JH (2006) Heat shock proteins form part of a danger signal cascade in response to lipopolysaccharide and GroEL. Clin Exp Immunol 145:183–189PubMedCrossRefGoogle Scholar
  18. Deepe GS Jr, Gibbons RS (2002a) Cellular and molecular regulation of vaccination with heat shock protein 60 from Histoplasma capsulatum. Infect Immun 70:3759–3767PubMedCrossRefGoogle Scholar
  19. Deepe GS Jr, Gibbons RS (2002b) Functional properties of the T cell receptor repertoire in responding to the protective domain of heat-shock protein 60 from Histoplasma capsulatum. J Infect Dis 186:815–822PubMedCrossRefGoogle Scholar
  20. Deepe GS Jr, Gibbons R, Brunner GD, Gomez FJ (1996) A protective domain of heat-shock protein 60 from Histoplasma capsulatum. J Infect Dis 174:828–834PubMedCrossRefGoogle Scholar
  21. Deepe GS Jr, Gibbons RS, Smulian AG (2008) Histoplasma capsulatum manifests preferential invasion of phagocytic subpopulations in murine lungs. J Leukoc Biol 84:669–678PubMedCrossRefGoogle Scholar
  22. Disalvo AF, Bigler WJ, Ajello L, Johnson JE, Palmer J (1970) Bat and soil studies for sources of histoplasmosis in Florida. Public Health Rep 85:1063–1069PubMedCrossRefGoogle Scholar
  23. Eissenberg LG, Goldman WE (1987) Histoplasma capsulatum fails to trigger release of superoxide from macrophages. Infect Immun 55:29–34PubMedGoogle Scholar
  24. Eissenberg LG, West JL, Woods JP, Goldman WE (1991) Infection of P388D1 macrophages and respiratory epithelial cells by Histoplasma capsulatum: selection of avirulent variants and their potential role in persistent histoplasmosis. Infect Immun 59:1639–1646PubMedGoogle Scholar
  25. Emmons CW (1950) Histoplasmosis: animal reservoirs and other sources in nature of the pathogenic fungus Histoplasma capsulatum. Am J Public Health 40:436–440CrossRefGoogle Scholar
  26. Emmons CW (1956a) Histoplasmosis in animals. Public Health Monogr 70:272–273Google Scholar
  27. Emmons CW (1956b) Isolation of Histoplasma capsulatum from soil. Public Health Monogr 70:237–239Google Scholar
  28. Emmons CW, Klite PD, Baer GM, Hill WB Jr (1966) Isolation of Histoplasma capsulatum from bats in the United States. Am J Epidemiol 84:103–109PubMedGoogle Scholar
  29. Gomez FJ, Gomez AM, Deepe GS Jr (1991) Protective efficacy of a 62-kilodalton antigen, HIS-62, from the cell wall and cell membrane of Histoplasma capsulatum yeast cells. Infect Immun 59:4459–4464PubMedGoogle Scholar
  30. Gomez FJ, Allendoerfer R, Deepe GS Jr (1995) Vaccination with recombinant heat shock protein 60 from Histoplasma capsulatum protects mice against pulmonary histoplasmosis. Infect Immun 63:2587–2595PubMedGoogle Scholar
  31. Goodwin RA Jr, Des Prez RM (1978) State of the art: histoplasmosis. Am Rev Respir Dis 117:929–956PubMedGoogle Scholar
  32. Goodwin RA, Loyd JE, Des Prez RM (1981) Histoplasmosis in normal hosts. Medicine (Baltimore) 60:231–266Google Scholar
  33. Guimaraes AJ, Nosanchuk JD, Zancope-Oliveira RM (2006) Diagnosis of Histoplasmosis. Braz J Microbiol 37:1–13PubMedCrossRefGoogle Scholar
  34. Guimaraes AJ, Hamilton AJ, de M Guedes HL, Nosanchuk JD, Zancope-Oliveira RM (2008) Biological function and molecular mapping of M antigen in yeast phase of Histoplasma capsulatum. PLoS One 3:e3449PubMedCrossRefGoogle Scholar
  35. Guimaraes AJ, Frases S, Gomez FJ, Zancope-Oliveira RM, Nosanchuk JD (2009) Monoclonal antibodies to heat shock protein 60 alter the pathogenesis of Histoplasma capsulatum. Infect Immun 77:1357–1367PubMedCrossRefGoogle Scholar
  36. Guimaraes AJ, de Cerqueira MD, Nosanchuk JD (2011a) Surface architecture of Histoplasma capsulatum. Front Microbiol 2:225PubMedCrossRefGoogle Scholar
  37. Guimaraes AJ, Frases S, Pontes B, de Cerqueira MD, Rodrigues ML, Viana NB, Nimrichter L, Nosanchuk JD (2011b) Agglutination of Histoplasma capsulatum by IgG monoclonal antibodies against Hsp60 impacts macrophage effector functions. Infect Immun 79:918–927PubMedCrossRefGoogle Scholar
  38. Guimaraes AJ, Martinez LR, Nosanchuk JD (2011c) Passive administration of monoclonal antibodies against H. capsulatum and other fungal pathogens. J Vis Exp (48). doi: 10.3791/2532, pii: 2532
  39. Guimaraes AJ, Nakayasu ES, Sobreira TJ, Cordero RJ, Nimrichter L, Almeida IC, Nosanchuk JD (2011d) Histoplasma capsulatum heat-shock 60 orchestrates the adaptation of the fungus to temperature stress. PLoS One 6:e14660Google Scholar
  40. Habich C, Burkart V (2007) Heat shock protein 60: regulatory role on innate immune cells. Cell Mol Life Sci 64:742–751PubMedCrossRefGoogle Scholar
  41. Habich C, Kempe K, van der Zee R, Burkart V, Kolb H (2003) Different heat shock protein 60 species share pro-inflammatory activity but not binding sites on macrophages. FEBS Lett 533:105–109PubMedCrossRefGoogle Scholar
  42. Habich C, Kempe K, Gomez FJ, Lillicrap M, Gaston H, van der Zee R, Kolb H, Burkart V (2006) Heat shock protein 60: identification of specific epitopes for binding to primary macrophages. FEBS Lett 580:115–120PubMedCrossRefGoogle Scholar
  43. Hunter-Lavin C, Davies EL, Bacelar MM, Marshall MJ, Andrew SM, Williams J (2004) Hsp70 release from peripheral blood mononuclear cells. Biochem Biophys Res Commun 324:511–517PubMedCrossRefGoogle Scholar
  44. Jethmalani SM, Henle KJ, Gazitt Y, Walker PD, Wang SY (1997) Intracellular distribution of heat-induced stress glycoproteins. J Cell Biochem 66:98–111PubMedCrossRefGoogle Scholar
  45. Kamei K, Brummer E, Clemons KV, Stevens DA (1992) Induction of stress protein synthesis in Histoplasma capsulatum by heat, low pH and hydrogen peroxide. J Med Vet Mycol 30:385–393PubMedCrossRefGoogle Scholar
  46. Kauffman CA (2007) Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 20:115–132PubMedCrossRefGoogle Scholar
  47. Lambowitz AM, Kobayashi GS, Painter A, Medoff G (1983) Possible relationship of morphogenesis in pathogenic fungus, Histoplasma capsulatum, to heat shock response. Nature 303:806–808PubMedCrossRefGoogle Scholar
  48. Lane TE, Wu-Hsieh BA, Howard DH (1994) Antihistoplasma effect of activated mouse splenic macrophages involves production of reactive nitrogen intermediates. Infect Immun 62:1940–1945PubMedGoogle Scholar
  49. Lazar-Molnar E, Gacser A, Freeman GJ, Almo SC, Nathenson SG, Nosanchuk JD (2008) The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. Proc Natl Acad Sci U S A 105:2658–2663PubMedCrossRefGoogle Scholar
  50. Li Z, Srivastava P (2004) Heat-Shock proteins. Curr Protoc Immunol 58:A.1T.1–A.1T.6Google Scholar
  51. Londero AT, Ramos C (1978) The status of histoplasmosis in Brazil. Mycopathologia 64:153–156PubMedCrossRefGoogle Scholar
  52. Long KH, Gomez FJ, Morris RE, Newman SL (2003) Identification of heat shock protein 60 as the ligand on Histoplasma capsulatum that mediates binding to CD18 receptors on human macrophages. J Immunol 170:487–494PubMedGoogle Scholar
  53. Macura N, Zhang T, Casadevall A (2007) Dependence of macrophage phagocytic efficacy on antibody concentration. Infect Immun 75:1904–1915PubMedCrossRefGoogle Scholar
  54. Maresca B (1995) Unraveling the secrets of Histoplasma capsulatum. A model to study morphogenic adaptation during parasite host/host interaction. Verh K Acad Geneeskd Belg 57:133–156PubMedGoogle Scholar
  55. Maresca B, Kobayashi GS (1989) Dimorphism in Histoplasma capsulatum: a model for the study of cell differentiation in pathogenic fungi. Microbiol Rev 53:186–209PubMedGoogle Scholar
  56. Maresca B, Kobayashi G (1993) Changes in membrane fluidity modulate heat shock gene expression and produced attenuated strains in the dimorphic fungus Histoplasma capsulatum. Arch Med Res 24:247–249PubMedGoogle Scholar
  57. Martinez LR, Mihu MR, Gacser A, Santambrogio L, Nosanchuk JD (2009) Methamphetamine enhances histoplasmosis by immunosuppression of the host. J Infect Dis 200:131–141PubMedCrossRefGoogle Scholar
  58. Meloan EL (1952) Histoplasmosis. Miss Doct 29:256–257PubMedGoogle Scholar
  59. Minchiotti G, Gargano S, Maresca B (1992) Molecular cloning and expression of hsp82 gene of the dimorphic pathogenic fungus Histoplasma capsulatum. Biochim Biophys Acta 1131:103–107PubMedCrossRefGoogle Scholar
  60. Mukherjee S, Feldmesser M, Casadevall A (1996) J774 murine macrophage-like cell interactions with Cryptococcus neoformans in the presence and absence of opsonins. J Infect Dis 173:1222–1231PubMedCrossRefGoogle Scholar
  61. Newman SL (2005) Interaction of Histoplasma capsulatum with human macrophages, dendritic cells, and neutrophils. Methods Mol Med 118:181–191PubMedGoogle Scholar
  62. Newman SL, Lemen W, Smulian AG (2011) Dendritic cells restrict the transformation of Histoplasma capsulatum conidia into yeasts. Med Mycol 49:356–364PubMedCrossRefGoogle Scholar
  63. Pfaller MA, Diekema DJ (2010) Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36:1–53PubMedCrossRefGoogle Scholar
  64. Sa-Nunes A, Medeiros AI, Nicolete R, Frantz FG, Panunto-Castelo A, Silva CL, Faccioli LH (2005) Efficacy of cell-free antigens in evaluating cell immunity and inducing protection in a murine model of histoplasmosis. Microbes Infect 7:584–592PubMedCrossRefGoogle Scholar
  65. Saibil HR (2008) Chaperone machines in action. Curr Opin Struct Biol 18:35–42PubMedCrossRefGoogle Scholar
  66. Scheckelhoff M, Deepe GS Jr (2002) The protective immune response to heat shock protein 60 of Histoplasma capsulatum is mediated by a subset of V beta 8.1/8.2+ T cells. J Immunol 169:5818–5826PubMedGoogle Scholar
  67. Shaner L, Gibney PA, Morano KA (2008) The Hsp110 protein chaperone Sse1 is required for yeast cell wall integrity and morphogenesis. Curr Genet 54:1–11PubMedCrossRefGoogle Scholar
  68. Shearer G Jr, Birge CH, Yuckenberg PD, Kobayashi GS, Medoff G (1987) Heat-shock proteins induced during the mycelial-to-yeast transitions of strains of Histoplasma capsulatum. J Gen Microbiol 133:3375–3382PubMedGoogle Scholar
  69. Smith CD (1971a) Nutritional factors that are required for the growth and sporulation of Histoplasma capsulatum. In: Ajello L, Chick EW, Furcolow ML (eds) Histoplasmosis. Proceedings of the second national conference. C Thomas, Springfield, pp 64–70Google Scholar
  70. Smith CD (1971b) The role of birds in the ecology of Histoplasma capsulatum. In: Ajello L, Chick EW, Furcolow ML (eds) Histoplasmosis. Proceedings of the second national conference. C Thomas, Springfield, pp 140–148Google Scholar
  71. Soltys BJ, Gupta RS (1997) Cell surface localization of the 60 kDa heat shock chaperonin protein (hsp60) in mammalian cells. Cell Biol Int 21:315–320PubMedCrossRefGoogle Scholar
  72. Strasser JE, Newman SL, Ciraolo GM, Morris RE, Howell ML, Dean GE (1999) Regulation of the macrophage vacuolar ATPase and phagosome-lysosome fusion by Histoplasma capsulatum. J Immunol 162:6148–6154PubMedGoogle Scholar
  73. Wheat J (1994) Histoplasmosis: recognition and treatment. Clin Infect Dis 19(Suppl 1):S19–S27PubMedCrossRefGoogle Scholar
  74. Wheat J (1996) Histoplasmosis in the acquired immunodeficiency syndrome. Curr Top Med Mycol 7:7–18PubMedGoogle Scholar
  75. Wheat J (1997) Histoplasmosis. Experience during outbreaks in Indianapolis and review of the literature. Medicine (Baltimore) 76:339–354CrossRefGoogle Scholar
  76. Wheat LJ (2001) Laboratory diagnosis of histoplasmosis: update 2000. Semin Respir Infect 16:131–140PubMedCrossRefGoogle Scholar
  77. Wheat LJ, Kauffman CA (2003) Histoplasmosis. Infect Dis Clin North Am 17:1–19PubMedCrossRefGoogle Scholar
  78. Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW, McKinsey DS, Loyd JE, Kauffman CA (2007) Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 45:807–825PubMedCrossRefGoogle Scholar
  79. Wolf AM (1987) Histoplasma capsulatum osteomyelitis in the cat. J Vet Intern Med 1:158–162PubMedCrossRefGoogle Scholar
  80. Wolf JE, Kerchberger V, Kobayashi GS, Little JR (1987) Modulation of the macrophage oxidative burst by Histoplasma capsulatum. J Immunol 138:582–586PubMedGoogle Scholar
  81. Wu-Hsieh B, Howard DH (1984) Inhibition of growth of Histoplasma capsulatum by lymphokine-stimulated macrophages. J Immunol 132:2593–2597PubMedGoogle Scholar
  82. Zancope-Oliveira RM, Morais e Silva Tavares P, de Muniz MM (2005) Genetic diversity of Histoplasma capsulatum strains in Brazil. FEMS Immunol Med Microbiol 45:443–449PubMedCrossRefGoogle Scholar
  83. Zeidberg LD, Ajello L, Dillon A, Runyon LC (1952) Isolation of Histoplasma capsulatum from soil. Am J Public Health 42:930–935CrossRefGoogle Scholar
  84. Zhou P, Seder RA (1998) CD40 ligand is not essential for induction of type 1 cytokine responses or protective immunity after primary or secondary infection with Histoplasma capsulatum. J Exp Med 187:1315–1324PubMedCrossRefGoogle Scholar
  85. Zhou P, Sieve MC, Bennett J, Kwon-Chung KJ, Tewari RP, Gazzinelli RT, Sher A, Seder RA (1995) IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-gamma. J Immunol 155:785–795PubMedGoogle Scholar
  86. Zhou P, Miller G, Seder RA (1998) Factors involved in regulating primary and secondary immunity to infection with Histoplasma capsulatum: TNF-alpha plays a critical role in maintaining secondary immunity in the absence of IFN-gamma. J Immunol 160:1359–1368PubMedGoogle Scholar
  87. Zugel U, Kaufmann SH (1999) Immune response against heat shock proteins in infectious diseases. Immunobiology 201:22–35PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Joshua Daniel Nosanchuk
    • 1
  • Allan Jefferson Guimarães
    • 2
  1. 1.Department of Microbiology and Immunology and Department of MedicineAlbert Einstein College of Medicine of Yeshiva UniversityBronxUSA
  2. 2.Instituto Biomédico, Dept. de Microbiologia e Parasitologia - MIPUniversidade Federal FluminenseNiteróiBrazil

Personalised recommendations