Molecular Pathology of Fungal Lung Infection

  • Michael R. McGinnis
  • Michael B. Smith
  • Abida K. Haque
Part of the Molecular Pathology Library book series (MPLB, volume 1)


Fungi are eukaryotic, unicellular or multicellular organisms that are larger and genomically more complex than bacteria. The fungal cell wall is complex and has polysaccharides, proteins, sugars, and glycoproteins. Plasma membranes of fungi contain ergosterol, which is the primary target for antifungal drugs such as amphotericin B. Although more than 1.3 million fungal species exist in the environment, only about 150 are pathogenic to humans.1 The virulence factors of fungi resemble those of bacteria, such as possession of a capsule, adhesion molecules, toxins, free radicals, and so forth. Thus, fungi can elicit acute exudative, necrotizing, and granulomatous reactions in tissues. Although some generalizations are possible, the diverse structural and antigenic properties of individual fungi produce unique patterns of infection in individual hosts.2,5


Fungal Infection Invasive Aspergillosis Aspergillus Fumigatus Invasive Fungal Infection Invasive Candidiasis 
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.


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  1. 1.
    Speth C, Rambach G, Lass-Florl C, et al. The role of complement in invasive fungal infections. Mycoses 2004;47:93–103.CrossRefPubMedGoogle Scholar
  2. 2.
    Waldorf AR. Pulmonary defense mechanisms against opportunistic fungal pathogens. Immunol Ser 1989;47:243–271.PubMedGoogle Scholar
  3. 3.
    Deepe GS, Bullock WE. Immunologic aspects of fungal pathogenesis. Eur J Clin Microbiol Dis 1990;9:567–579.CrossRefGoogle Scholar
  4. 4.
    Shoham S, Levitz SM. The immune response to fungal infections. Br J Haematol 2005;129:569–582.CrossRefPubMedGoogle Scholar
  5. 5.
    Levitz SM. Overview of host defenses in fungal infections. Clin Infect Dis 1992;14(Suppl 1):S37–S42.PubMedGoogle Scholar
  6. 6.
    Crameri R, Blaser K. Allergy and immunity to fungal infections and colonization. Eur Respir J 2002;19:151–157.CrossRefPubMedGoogle Scholar
  7. 7.
    McCormack FX, Gibbons R, Ward SR, et al. Macrophageindependent fungicidal action of the pulmonary collectins. J Biol Chem 2003;278:36250–36256.CrossRefPubMedGoogle Scholar
  8. 8.
    Romani L. Immunity to fungal infections. Nat Rev Immunol 2004;4:1–23.CrossRefPubMedGoogle Scholar
  9. 9.
    Huffnagle GB, Deepe GS. Innate and adaptive determinants of host susceptibility to medically important fungi. Curr Opin Microbiol 2003;6:344–350.CrossRefPubMedGoogle Scholar
  10. 10.
    Mambula SS, Sau K, Henneke P, et al. Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus. J Biol Chem 2002;277:39320–39326.CrossRefPubMedGoogle Scholar
  11. 11.
    Mansour MK, Levitz SM. Interactions of fungi with phagocytes. Curr Opin Microbiol 2002;5:359–365.CrossRefPubMedGoogle Scholar
  12. 12.
    Roilides E, Dignani MC, Anaissie EJ, Rex JH. The role of immunoreconstitution in the management of refractory opportunistic infections. Med Mycol 1998a;36(Suppl 1):12–25.PubMedGoogle Scholar
  13. 13.
    Lohmeyer J. Role of hematopoietic growth factors and cytokines in host defense against fungal infections. Mycoses 1997;40(Suppl 2):37–39.CrossRefPubMedGoogle Scholar
  14. 14.
    Schaffner A, Douglas H, Braude A. Selective protection against conidia by mononuclear and mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. J Clin Invest 1982;69:617–631.CrossRefPubMedGoogle Scholar
  15. 15.
    Romani L. The T cell response against fungal infections. Curr Opin Immunol 1997;9:484–490.CrossRefPubMedGoogle Scholar
  16. 16.
    Trinchieri G, Kubin M, Bellone G, Cassatella MC. Cytokine cross-talk between phagocytic cells and lymphocytes: relevance for differentiation/activation of phagocytic cells and regulation of adaptive immunity. J Cell Biochem 1993;53:301–308.CrossRefPubMedGoogle Scholar
  17. 17.
    Antachopoulos C, Roilides E. Cytokines and fungal infections. Br J Hematol 2005;129:583–596.CrossRefGoogle Scholar
  18. 18.
    Montagnoli C, Bacci A, Bozza S, et al. B7/CD28-dependent CD4+CD25+ regulatory T cells are essential components of the memory-protective immunity to Candida albicans. J Immunol 2002;169:6298–6308.PubMedGoogle Scholar
  19. 19.
    Ausiello CM, Urbani F, Gessani S, et al. Cytokine gene expression in human peripheral blood mononuclear cells stimulated by mannoprotein constituents from Candida albicans. Infect Immun 1993;61:4105–4111.PubMedGoogle Scholar
  20. 20.
    Bauman SK, Nicholas KL, Murphy JW. Dendritic cells in the induction of protective and nonprotective anticryptococcal cell-mediated immune response. J Immunol 1998;165:158–167.Google Scholar
  21. 21.
    Braedel S, Radsak M, Einsele H, et al. Aspergillus fumigatus antigens activate innate immune cells via toll-like receptors 2 and 4. Br J Hematol 2004;125:392–399.CrossRefGoogle Scholar
  22. 22.
    Huang Q, Liu D, Majewski P, et al. The plasticity of dendritic cell responses to pathogens and their components. Science 2001;294:870–875.CrossRefPubMedGoogle Scholar
  23. 23.
    Romani L, Bistoni F, Puccetti P. Fungi, dendritic cells and receptors: a host perspective of fungal virulence. Trends Microbiol 2002;10:508–514.CrossRefPubMedGoogle Scholar
  24. 24.
    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.CrossRefPubMedGoogle Scholar
  25. 25.
    Netea MG, Van Der Graaf CA, Vonk AG, et al. The role of toll-like receptors (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J Infect Dis 2002;185:1483–1489.CrossRefPubMedGoogle Scholar
  26. 26.
    Roilides E, Tsaparidou S, Kadiltsoglou I, et al. Interleukin-12 enhances antifungal activity of human mononuclear phagocytes against Aspergillus fumigatus: implications for a gamma interferon-independent pathway. Infect Immun 1999;67:3047–3050.PubMedGoogle Scholar
  27. 27.
    Cenci E, Mencacci A, Del Sero G, et al. IFN-gamma is required for IL-12 responsiveness in mice with Candida albicans infection. J Immunol 1998a;161:3543–3550.PubMedGoogle Scholar
  28. 28.
    Cassone A, Conti S, De Bernardis F, Polonelli L. Antibodies, killer toxins and antifungal immunoprotection: a lesson from nature?. Immunol Today 1997;18:164–169.CrossRefPubMedGoogle Scholar
  29. 29.
    Nosanchuck JD. Protective antibodies and endemic dimorphic fungi. Curr Mol Med 2005;5:435–442.CrossRefGoogle Scholar
  30. 30.
    Magliani W, Conti S, Arseni S, et al. Antibody-mediated protective immunity in fungal infections. New Microbiol 2005;28:299–309.PubMedGoogle Scholar
  31. 31.
    Horner SE, Helbling A, Salvaggio JE, Lehrer SB. Fungal allergens. Clin Microbiol Rev 1995;8:161–179.PubMedGoogle Scholar
  32. 32.
    Knutsen AP, Mueller KR, Levine AD, et al. Asp f 1 CD4+ TH2-like T-cell lines in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 1994;94:215–221.CrossRefPubMedGoogle Scholar
  33. 33.
    Hemmann S, Menz G, Ismail C, et al. Skin test reactivity to 2 recombinant Aspergillus fumigatus allergens in A. fumigatus-sensitized asthmatic subjects allows diagnostic separation of allergic bronchopulmonary aspergillosis from fungal sensitization. J Allergy Clin Immunol 1999;104:601–607.CrossRefPubMedGoogle Scholar
  34. 34.
    Haque AK. Pathology of common pulmonary fungal infections. J Thorac Imaging 1992;7(4):1–11.CrossRefPubMedGoogle Scholar
  35. 35.
    Saubolle MA. Fungal pneumonias. Semin Respir Infect 2000;15(2):162–177.CrossRefPubMedGoogle Scholar
  36. 36.
    Walsh TJ, Hiemenz JW, Siebel NL, et al. Amphotericin B lipid complex for invasive fungal infections: analysis on safety and efficacy in 556 cases. Clin Infect Dis 1998;26:1383–1396.CrossRefPubMedGoogle Scholar
  37. 37.
    American Thoracic Society statement. Fungal infections in HIV infected persons. Am J Respir Crit Care Med 1995;152:816.Google Scholar
  38. 38.
    Walsh TJ, Groll A, Hiemenz J, et al. Infections due to emerging and uncommon medically important fungal pathogens. Clin Microbiol Infect 2004;10(Suppl 1):48–66.CrossRefPubMedGoogle Scholar
  39. 39.
    Hawkins C, Armstrong D. Fungal infections in the immunocompromised host. Clin Hematol 1984;13:599–630.Google Scholar
  40. 40.
    Murray, JF, Mills J. Pulmonary infectious complications of human immunodeficiency virus infection. Part II. Am Rev Respir Dis 1990;141:1582.PubMedGoogle Scholar
  41. 41.
    Crum NF, Lederman ER, Stafford CM, et al. Coccidioidomycosis: a descriptive survey of a reemerging disease. Clinical characteristics and current controversies. Medicine (Baltimore) 2004;83(3):149–175.CrossRefGoogle Scholar
  42. 42.
    Grieco MH. Humoral and cellular responses to infection. In Grieco MH, ed. Infections in the Abnormal Host. New York: Yorke Medical; 1980:131–304.Google Scholar
  43. 43.
    Elliott K, Whelan J, eds. Enzyme Defects and Immune Dysfunction. Ciba Foundation Symposium No. 68. Amsterdam: Excerpta Medica; 1979.Google Scholar
  44. 44.
    Alexander BD. Diagnosis of fungal infection: new technologies for the mycology laboratory. Transpl Infect Dis 2002;4(Suppl 3):32–37.CrossRefPubMedGoogle Scholar
  45. 45.
    Chen KY, Ko SC, Hsueh PR, et al. Pulmonary fungal infection: emphasis on microbiological spectrum, patient outcome, and prognostic factors. Chest 2001;120:177–184.CrossRefPubMedGoogle Scholar
  46. 46.
    Liu ZY, Sheng RY, Li XL, et al. Nosocomial fungal infections, analysis of 149 cases. Zhonghua Yi Xue Za Zhi 2003;83(5):399–402.PubMedGoogle Scholar
  47. 47.
    Balajee SA, Gribskov JL, Hanley E, et al. Aspergillus lentulus sp. nov., a new sibling species of A. fumigatus. Eukaryot Cell 2005;4(3):625–632.CrossRefPubMedGoogle Scholar
  48. 48.
    Varga J, Vida Z, Toth B, et al. Phylogenetic analysis of newly described Neosartorya species. Antonie van Leeuwenhoek 2000;77:235–239.CrossRefPubMedGoogle Scholar
  49. 49.
    Katz ME, Dougall AM, Weeks K, Cheetham BF. Multiple genetically distinct groups revealed among clinical isolates identified as atypical Aspergillus fumigatus. J Clin Microbiol 2005;43(2):551–555.CrossRefPubMedGoogle Scholar
  50. 50.
    Balajee SA, Gribskov J, Brandt M, et al. Mistaken identity: Neosartorya pseudofischeri and its anamorph masquerading as Aspergillus fumigatus. J Clin Microbiol 2005;43(12):5996–5999.CrossRefPubMedGoogle Scholar
  51. 51.
    Nierman WC, Pain A, Anderson MJ, et al. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 2005;438(7071):1151–1156.CrossRefPubMedGoogle Scholar
  52. 52.
    Pringle A, Baker DM, Platt JL, et al. Cryptic speciation in the cosmopolitan and clonal human pathogenic fungus Aspergillus fumigatus. Evol Int J Org Evol 2005;59(9):1886–1899.Google Scholar
  53. 53.
    Hong SB, Shin HD, Frisvad JC, Samson RA. Polyphasic taxonomy of Aspergillus fumigatus and related species. Mycologia 2005;97(6):1316–1329.CrossRefPubMedGoogle Scholar
  54. 54.
    Fischer MG, Koenig GL, White TJ, Taylor JW. Molecular and phenotypic description of Coccidioides posadasii sp. nov., previously recognized as the non-California population of Coccidioides immitis. Mycologia 2002;94(1):73–84.CrossRefGoogle Scholar
  55. 55.
    Kasuga T, Taylor JW, White TJ. Phylogenetic relationships of varieties and geographical groups of the human pathogenic fungus Histoplasma capsulatum Darling. J Clin Microbiol 1999;37(3):653–663.PubMedGoogle Scholar
  56. 56.
    Komori T, Sano A, Yarita K, et al. Phylogenetic analysis of Histoplasma capsulatum based on partial sequence of the D1/D2 region of the 28S rRNA gene. Nippon Ishinkin Gakkai Zasshi 2005;46(4):291–295.PubMedGoogle Scholar
  57. 57.
    Paris S, Debeaupuis JP, Crameri R, et al. Conidial hydrophobins of Aspergillus fumigatus. Appl Environ Microbiol 2003;69(3):1581–1588.CrossRefPubMedGoogle Scholar
  58. 58.
    Kwon-Chung KJ, Hill WB, Bennett JE. New, special stain for histopathological diagnosis of cryptococcosis. J Clin Microbiol 1981;13(2):383–387.PubMedGoogle Scholar
  59. 59.
    Gomez BL, Nosanchuk JD. Melanin and fungi. Curr Opin Infect Dis 2003;16(2):91–96.PubMedGoogle Scholar
  60. 60.
    Nosanchuk JD, Gomez BL, Younchim S, et al. Histoplasma capsulatum synthesizes melanin-like pigments in vitro and during mammalian infection. Infect Immun 2002;70(9):5124–5131.CrossRefPubMedGoogle Scholar
  61. 61.
    Newman SL, Gootee L, Hilty J, Morris RE. Human macrophages do not require phagosome acidification to mediate fungistatic/fungicidal activity against Histoplasma capsulatum. J Immunol 2006;176(3):1806–1813.PubMedGoogle Scholar
  62. 62.
    Lewis RE, Wiederhold NP, Lionakis MS, et al. Frequency and species distribution of gliotoxin-producing Aspergillus isolates recovered from patients at a tertiary-care cancer center. J Clin Microbiol 2005;43(12):6120–6122.CrossRefPubMedGoogle Scholar
  63. 63.
    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(Pt 8):719–725.CrossRefPubMedGoogle Scholar
  64. 64.
    Cox RA, Magee DM. Coccidioidomycosis: host response and vaccine development. Clin Microbiol Rev 2004;17(4):804–803.CrossRefPubMedGoogle Scholar
  65. 65.
    Woods JP, Heinecke EL, Luecke JW, et al. Pathogenesis of Histoplasma capsulatum. Semin Respir Infect 2001;16(2):91–101.CrossRefPubMedGoogle Scholar
  66. 66.
    Bialek R, Konrad F, Kern J, et al. PCR based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue. J Clin Pathol 2005;58(11):1180–1184.CrossRefPubMedGoogle Scholar
  67. 67.
    Rickerts V, Just-Nubling G, Konrad F, et al. Diagnosis of invasive aspergillosis and mucormycosis in immunocompromised patients by seminested PCR assay of tissue samples. Eur J Clin Microbiol Infect Dis 2006;25(1):8–13.CrossRefPubMedGoogle Scholar
  68. 68.
    Playford EG, Kong F, Sun Y, et al. Simultaneous detection and identification of Candida, Aspergillus, and Cryptococcus species by reverse line blot hybridization. J Clin Microbiol 2006;44(3):876–880.CrossRefPubMedGoogle Scholar
  69. 69.
    Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med 2006;173(7):707–717.CrossRefPubMedGoogle Scholar
  70. 70.
    Naber PS. Molecular pathology—diagnosis of infectious disease. N Engl J Med 1994;331:1212–1215.CrossRefPubMedGoogle Scholar
  71. 71.
    Symposium: Molecular techniques in diagnostic pathology. Hum Pathol 1994;25:555–614.Google Scholar
  72. 72.
    Obayashi T, Yoshida M, Mori T, et al. Plasma (1→3)-beta-D-glycan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet 1995;345:17–20.CrossRefPubMedGoogle Scholar
  73. 73.
    Mori T, Ikemoto H, Matsumura M, et al. Evaluation of plasma (1→3)-beta-D-glucan measurement by the kinetic turbidimetric Limulus test, for the clinical diagnosis of mycotic infections. Eur J Clin Chem Clin Biochem 1997;35:553–560.PubMedGoogle Scholar
  74. 74.
    Pfaller MA, Cabezudo I, Buschelman B, et al. Value of the Hybritech ICON Candida assay in the diagnosis of invasive candidiasis in high-risk patients. Diagn Microbiol Infect Dis 1993;16:53–60.CrossRefPubMedGoogle Scholar
  75. 75.
    Lindsley MD, Hurst SF, Iqbal NJ, et al. Rapid identification of dimorphic and yeast-like fungal pathogens using specific DNA probes. J Clin Microbiol 2001;39(10):3505–3511.CrossRefPubMedGoogle Scholar
  76. 76.
    Raad I, Hanna H, Sumoza D, Albitar M. Polymerase chain reaction on blood for the diagnosis of invasive pulmonary aspergillosis in cancer patients. Cancer 2002;94:1032–1036.CrossRefPubMedGoogle Scholar
  77. 77.
    Costa C, Costa JM, Desterke C, et al. Real-time PCR coupled with automated DNA extraction and detection of galactomannan antigen in serum by enzyme-linked immunosorbent assay for diagnosis of invasive aspergillosis. J Clin Microbiol 2002;40(6):2224–2227.CrossRefPubMedGoogle Scholar
  78. 78.
    Kraus PR, Boily MJ, Giles SS, et al. Identification of Cryptococcus neoformans temperature-regulating genes with a genomic-DNA microarray. Eukaryot Cell 2004;3:1249–1260.CrossRefPubMedGoogle Scholar
  79. 79.
    Raad I, Hanna H, Sumoza D, Albitar M. Polymerase chain reaction on blood for the diagnosis of invasive pulmonary aspergillosis in cancer patients. Cancer 2002;94:1032–1036.CrossRefPubMedGoogle Scholar
  80. 80.
    Maertens J, Van Eldere J, Verhaegen J, et al. Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allergenic stem cell transplant recipients. J Infect Dis 2002;186:1297–306.CrossRefPubMedGoogle Scholar
  81. 81.
    Hinrikson HP, Hurst SF, Lott TJ, et al. Assessment of ribosomal large-subunit D1–D2, internal transcribed spacer 1, and internal transcribed spacer 2 regions as targets for molecular identification of medically important Aspergillus species. J Clin Microbiol 2005;43(5):2092–2103.CrossRefPubMedGoogle Scholar
  82. 82.
    Chiller TM, Galgiani JN, Stevens DA. Coccidioidomycosis. Infect Dis Clin North Am 2003;7(1):41–45.CrossRefGoogle Scholar
  83. 83.
    Wheat LJ. Current diagnosis of histoplasmosis. Trends Microbiol 2003;11(10):488–494.CrossRefGoogle Scholar
  84. 84.
    Wheat LJ, Garringer T, Brizendine E, Connolly P. Diagnosis of histoplasmosis by antigen detection based upon experience at the histoplasmosis reference laboratory. Diagn Microbiol Infect Dis 2002;43(1):29–37.CrossRefPubMedGoogle Scholar
  85. 85.
    Polonelli L, Casadevall A, Han Y, et al. The efficacy of acquired humoral and cellular immunity in the prevention and therapy of experimental fungal infections. Med Mycol 2000;38:281–292.PubMedGoogle Scholar
  86. 86.
    Dan JM, Levitz SM. Prospects for development of vaccines against fungal diseases. Drug Resist Update 2006;9(3):105–110.CrossRefGoogle Scholar
  87. 87.
    Casadevall A, Pirofski LA. Polysaccharide-containing conjugate vaccines for fungal diseases. Trends Mol Med 2006;12(1):6–9.CrossRefPubMedGoogle Scholar
  88. 88.
    Stevens DA. Vaccinate against aspergillosis! A call to arms of the immune system. Clin Infect Dis 2004;38(8):1131–1136.CrossRefPubMedGoogle Scholar
  89. 89.
    Deepe GS Jr, Wuthrich M, Klein BS. Progress in vaccination for histoplasmosis and blastomycosis: coping with cellular immunity. Med Mycol 2005;43(5):381–389.CrossRefPubMedGoogle Scholar
  90. 90.
    Adderson E. Histoplasmosis. Pediatr Infect Dis J 2006;25(1):73–74.CrossRefPubMedGoogle Scholar
  91. 91.
    Keating GM. Posaconazole. Drugs 2005;65(11):1553–67;1568–1569.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Michael R. McGinnis
    • 1
  • Michael B. Smith
    • 1
  • Abida K. Haque
    • 2
    • 3
  1. 1.Department of PathologyUniversity of Texas Medical BranchGalvestonUSA
  2. 2.Pathology and Laboratory MedicineWeill Medical College of Cornell UniversityNew York
  3. 3.Department of PathologySan Jacinto Methodist HospitalBaytownUSA

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