Medical Microbiology and Immunology

, Volume 192, Issue 4, pp 225–229 | Cite as

Programmed cell death in thymus during experimental paracoccidioidomycosis

  • Paula C. S. SoutoEmail author
  • Vânia N. Brito
  • Jacy Gameiro
  • Maria Alice da Cruz-Höfling
  • Liana Verinaud
Original Investigation


Many works have shown that immunosuppressive effects induced by systemic mycosis can be related to primary lymphoid organ damage. Previous studies in our laboratory showed that Paracoccidioides brasiliensis was able to invade the thymus, inducing a severe atrophy with significant reduction of cortical area along with a loss of cortico-medullary boundary. The objective of the present study was to investigate whether thymic atrophy is caused by programmed cell death (PCD) and to examine the ultrastructural characteristics of the thymus in experimentally infected BALB/c mice. The results revealed an eightfold increase in the apoptotic index occurring by day 5 post infection, i.e., during early stages of the infection, shown by immunohistochemistry. In addition, typical cell alterations of autophagic PCD were observed by transmission electron microscopy. Taken together, these results reinforce the idea that thymic alterations may be involved in the immunosuppressive phenomenon frequently associated with paracoccidioidomycotic infection.


Paracoccidioides brasiliensis Thymus TUNEL Electron microscopy Programmed cell death 



The authors wish to thank Prof. Áureo Tatsumi Yamada for his generous support throughout this study. This work was supported by grants from Fundo de Apoio ao Ensino e à Pesquisa da Unicamp (FAEP/UNICAMP 0682/00) and Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP 98/09660-1; 00/00996-9).


  1. 1.
    Alvarez F, Vellena A, Zapata A, Razquim B (1995) Histopathology of the thymus in Saprolegnia-infected wild brown trout, Salmo trutta L. Vet Immunol Immunopathol 47:163–172CrossRefGoogle Scholar
  2. 2.
    Benard G, Mendes-Giannini MJS, Juvenali M, Miranda ET, Duarte AJS (1997) Immunosuppression in paracoccidioidomycosis: T cell hyporesponsivenes to two Paracoccidioides brasiliensis glycoproteins that elicit strong humoral immune response. J Infect Dis 175:1263–1267Google Scholar
  3. 3.
    Brito VN, Souto PCS, Cruz-Höffling MA, Ricci LC, Verinaud L (2002) Thymic invasion and atrophy induced by Paracoccidioides brasiliensis in BALB/c mice. Med Mycol 41:1–5Google Scholar
  4. 4.
    Brummer E, Castaneda E, Restrepo A (1993) Paracoccidioidomycosis: an update. Clin Microbiol Rev 6:89–117Google Scholar
  5. 5.
    Cacere CR, Romano CC, Mendes-Giannini MJS, Duarte AJS, Benard G (2002) The role of apoptosis in the antigen-specific T cell hyporesponsiveness of paracoccidioidomycosis patients. Clin Immunol 105:215–222CrossRefGoogle Scholar
  6. 6.
    Castaneda E, Brummer E, Pappagianis D, Stevens DA (1988) Impairment of cellular but not humoral responses in chronic pulmonary and disseminated paracoccidioidomycosis in mice. Infect Immun 56:1771–1777Google Scholar
  7. 7.
    Clarke, PGH (1990) Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl) 181:195–213Google Scholar
  8. 8.
    Franco M, Mendes RP, Moscadi-Bacchi M (1989) Paracoccidioidomycosis. Baillière's Clin Trop Med Comm Dis 4:185–220Google Scholar
  9. 9.
    Goldani LZ, Sugar AM (1995) Paracoccidioidomycosis and AIDS: an overview. Clin Infect Dis 21:1275–1281Google Scholar
  10. 10.
    Islam Z, Masahiro N, Yoshizawa T, Yamauchi K, Sakato N (1998) T-2 toxin induces thymic apoptosis in vivo in mice. Toxicol Appl Pharmacol 148:205–214CrossRefGoogle Scholar
  11. 11.
    Isogai E, Isogai H, Kimura K, Fujii N, Takagi S, Hirose K, Hayashi M (1996) In vivo induction of apoptosis and immune response in mice by administration of lypopolysaccharide from Porphyromonas gingivalis. Infect Immun 64:1461–1466Google Scholar
  12. 12.
    Jimenez-Finkel BE, Murphy JW (1988) Characterization of efferent T suppressor cells induced by Paracoccidioides brasiliensis-specific afferent T suppressor cells. Infect Immun 56:744–750Google Scholar
  13. 13.
    Kerr JFR, Searle J, Harmon BV, Bishop CJ (1987) Apoptosis. In: Potten CS (ed) Perspectives on mammalian cell death. Oxford University Press, New York, pp 93–128Google Scholar
  14. 14.
    Knaapen MWM, Davies MJ, De Bie M, Haven AJ, Martinet W, Kockx MM (2001) Apoptotic versus autophagic cell death in heart failure. Cardiovasc Res 51:304–312CrossRefGoogle Scholar
  15. 15.
    Ozeki Y, Kaneda K, Fujiwara N, Morinoto M, Oka S, Yano I (1997) In vivo induction of apoptosis in the thymus by administration of mycobacterial cord factor (trehalose 6,6'-dimycolate). Infect Immun 65:1793–1799PubMedGoogle Scholar
  16. 16.
    Patiño JAG, Ivanov VN, Lacy E, Elkon KB, Marino MW, Nikolic-Zugic J (2000) TNF-α is the critical mediator of the cyclic AMP-induced apoptosis of CD8+4+ double-positive thymocytes. J Immunol 164:1689–1694PubMedGoogle Scholar
  17. 17.
    Price P, Olver SD, Gibbons AE, Teo HK, Shellam GR (1993) Characterization of thymic involution induced by murine cytomegalovirus infection. Immunol Cell Biol 71:155–165PubMedGoogle Scholar
  18. 18.
    Roblebo MA, Graybill JR, Ahrens J, Restrepo A, Drutz DJ, Roblebo M (1982) Host defense against experimental paracoccidioidomycosis. Am Rev Respir Dis 125:583–567Google Scholar
  19. 19.
    Sano A, Nobuyuki K, Iabuki K (1993) A comparative study of four different staining methods for estimation of live yeast form cells of P. brasiliensis. Mycopathologia 124:157–161Google Scholar
  20. 20.
    Savino W, Leite-de-Moraes MC, Hontebeyrie-Joskowicz M, Dardenne M (1989) Studies on thymus in Chagas' disease I. Changes in the thymus microenvironment in mice acutely infected with Trypanosoma cruzi. Eur J Immunol 19:1727–1733Google Scholar
  21. 21.
    Silva MR, Marques AS, Campos DS, Taboada DC, Soares GH, Brascher HM, Vargens-Neto JR, Cruz MQ, Labarther NV, Rocha GL, Lima AO (1981) Imunologia na paracoccidioidomicose. An Bras Dermatol 56:227–234Google Scholar
  22. 22.
    Singer-Vermes LM, Caldeira CB, Burger E, Calich VLG (1993) Experimental murine paracoccidioidomycosis: relationship among the dissemination of infection, humoral and cellular responses. Clin Exp Immunol 94:75–79Google Scholar
  23. 23.
    Sotomayor CE, Rubistein HR, Cervi L, Riera CM, Masih DT (1989) Immunosuppression in experimental cryptococcosis in rats: induction of thymic suppressor cells. Mycopathologia 108:5–10Google Scholar
  24. 24.
    Sutton P, Newcombe NR, Waring P, Müllbacher A (1994) In vivo immunosuppressive activity of gliotoxin, a metabolite produced by human pathogenic fungi. Infect Immun 62:1192–1198Google Scholar
  25. 25.
    Teixeira HC, Calich VLG, Singer-Vermes LM, D'Imperio-Lima MR, Russo M (1987) Experimental paracoccidioidomycosis: early immunosuppression occurs in susceptible mice after infection with pathogenic fungi. Braz J Med Biol Res 20:367–369Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Paula C. S. Souto
    • 1
    Email author
  • Vânia N. Brito
    • 1
  • Jacy Gameiro
    • 1
  • Maria Alice da Cruz-Höfling
    • 2
  • Liana Verinaud
    • 1
  1. 1.Departamento de Microbiologia e Imunologia, Instituto de BiologiaUniversidade Estadual de Campinas (UNICAMP)Campinas-SPBrazil
  2. 2.Departamento de Histologia e Embriologia, Instituto de BiologiaUniversidade Estadual de Campinas (UNICAMP)Campinas-SPBrazil

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