Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1997 Aug;65(8):3422–3429. doi: 10.1128/iai.65.8.3422-3429.1997

Effects of granulocyte and granulocyte-macrophage colony-stimulating factors in a neutropenic murine model of trichosporonosis.

H Muranaka 1, M Suga 1, K Nakagawa 1, K Sato 1, Y Gushima 1, M Ando 1
PMCID: PMC175484  PMID: 9234807

Abstract

We produced disseminated trichosporonosis in a neutropenic murine model with Trichosporon asahii, which was identified by DNA relatedness analysis. We then assessed the efficacy of granulocyte colony-stimulating factor (G-CSF) (30 to 100 microg/kg of body weight per day) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.8 to 2 microg/kg x day). The administration of G-CSF either before or after infection improved the survival rate from less than 25% up to 100% (P < 0.05). The effects of G-CSF on organ clearance and histological examinations were most remarkable in the lungs. The levels of tumor necrosis factor alpha (TNF-alpha) in bronchoalveolar lavage fluid (BALF) of neutropenic and G-CSF-pretreated mice were 60 +/- 6 ng/ml and 18 +/- 6 pg/ml, respectively, at 24 h after infection. Immunohistologically, alveolar macrophages proved to be the main source of TNF-alpha in BALF. GM-CSF increased neutrophil counts less significantly than did G-CSF and increased the lethality (P < 0.05) with a high level of TNF-alpha in BALF. Expecting to inhibit TNF-alpha, we administered anti-TNF-alpha intraperitoneally at the dose completely inhibiting TNF-alpha in plasma (2 x 10(4) U), but the TNF-alpha level in BALF and the lethality increased. Though the number of neutrophils at the early stage of infection appeared to be the most critical, the results suggest that other host defense mechanisms, such as TNF-alpha overproduction in the lungs, have an important role in the prognosis of trichosporonosis.

Full Text

The Full Text of this article is available as a PDF (494.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anaissie E. J., Hachem R., Karyotakis N. C., Gokaslan A., Dignani M. C., Stephens L. C., Tin-U C. K. Comparative efficacies of amphotericin B, triazoles, and combination of both as experimental therapy for murine trichosporonosis. Antimicrob Agents Chemother. 1994 Nov;38(11):2541–2544. doi: 10.1128/aac.38.11.2541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ando M., Arima K., Yoneda R., Tamura M. Japanese summer-type hypersensitivity pneumonitis. Geographic distribution, home environment, and clinical characteristics of 621 cases. Am Rev Respir Dis. 1991 Oct;144(4):765–769. doi: 10.1164/ajrccm/144.4.765. [DOI] [PubMed] [Google Scholar]
  3. Arai K. I., Lee F., Miyajima A., Miyatake S., Arai N., Yokota T. Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem. 1990;59:783–836. doi: 10.1146/annurev.bi.59.070190.004031. [DOI] [PubMed] [Google Scholar]
  4. Armstrong L., Jordan N., Millar A. Interleukin 10 (IL-10) regulation of tumour necrosis factor alpha (TNF-alpha) from human alveolar macrophages and peripheral blood monocytes. Thorax. 1996 Feb;51(2):143–149. doi: 10.1136/thx.51.2.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bodey G. P., Anaissie E., Gutterman J., Vadhan-Raj S. Role of granulocyte-macrophage colony-stimulating factor as adjuvant therapy for fungal infection in patients with cancer. Clin Infect Dis. 1993 Oct;17(4):705–707. doi: 10.1093/clinids/17.4.705. [DOI] [PubMed] [Google Scholar]
  6. Buret A., Dunkley M. L., Pang G., Clancy R. L., Cripps A. W. Pulmonary immunity to Pseudomonas aeruginosa in intestinally immunized rats roles of alveolar macrophages, tumor necrosis factor alpha, and interleukin-1 alpha. Infect Immun. 1994 Dec;62(12):5335–5343. doi: 10.1128/iai.62.12.5335-5343.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Calandra T., Baumgartner J. D., Grau G. E., Wu M. M., Lambert P. H., Schellekens J., Verhoef J., Glauser M. P. Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-alpha, and interferon-gamma in the serum of patients with septic shock. Swiss-Dutch J5 Immunoglobulin Study Group. J Infect Dis. 1990 May;161(5):982–987. doi: 10.1093/infdis/161.5.982. [DOI] [PubMed] [Google Scholar]
  8. Chen G. H., Curtis J. L., Mody C. H., Christensen P. J., Armstrong L. R., Toews G. B. Effect of granulocyte-macrophage colony-stimulating factor on rat alveolar macrophage anticryptococcal activity in vitro. J Immunol. 1994 Jan 15;152(2):724–734. [PubMed] [Google Scholar]
  9. Denis M. Colony-stimulating factors increase resistance to atypical mycobacteria in resistant mice, whereas they decrease resistance in susceptible strains of mice. J Leukoc Biol. 1991 Sep;50(3):296–302. doi: 10.1002/jlb.50.3.296. [DOI] [PubMed] [Google Scholar]
  10. Dörlemann A., Listemann H., Iglauer F. Invasive Trichosporon beigelii infection in immunosuppressed rats. Mycoses. 1994 Mar-Apr;37(3-4):109–116. doi: 10.1111/j.1439-0507.1994.tb00785.x. [DOI] [PubMed] [Google Scholar]
  11. Futenma M., Kawakami K., Saito A. Production of tumor necrosis factor-alpha in granulocytopenic mice with pulmonary candidiasis and its modification with granulocyte colony-stimulating factor. Microbiol Immunol. 1995;39(6):411–417. doi: 10.1111/j.1348-0421.1995.tb02221.x. [DOI] [PubMed] [Google Scholar]
  12. Gokaslan A., Anaissie E. A novel murine model of disseminated trichosporonosis. Infect Immun. 1992 Aug;60(8):3339–3344. doi: 10.1128/iai.60.8.3339-3344.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Grauer M. E., Bokemeyer C., Bautsch W., Freund M., Link H. Successful treatment of a Trichosporon beigelii septicemia in a granulocytopenic patient with amphotericin B and granulocyte colony-stimulating factor. Infection. 1994 Jul-Aug;22(4):283–286. doi: 10.1007/BF01739918. [DOI] [PubMed] [Google Scholar]
  14. Guého E., Improvisi L., de Hoog G. S., Dupont B. Trichosporon on humans: a practical account. Mycoses. 1994 Jan-Feb;37(1-2):3–10. doi: 10.1111/j.1439-0507.1994.tb00277.x. [DOI] [PubMed] [Google Scholar]
  15. Guého E., Smith M. T., de Hoog G. S., Billon-Grand G., Christen R., Batenburg-van der Vegte W. H. Contributions to a revision of the genus Trichosporon. Antonie Van Leeuwenhoek. 1992 May;61(4):289–316. doi: 10.1007/BF00713938. [DOI] [PubMed] [Google Scholar]
  16. Guého E., de Hoog G. S., Smith M. T. Neotypification of the genus Trichosporon. Antonie Van Leeuwenhoek. 1992 May;61(4):285–288. doi: 10.1007/BF00713937. [DOI] [PubMed] [Google Scholar]
  17. Hospenthal D., Belay T., Lappin P., Rogers A., Kennedy M. Disseminated trichosporonosis in a neutropenic murine model. Mycopathologia. 1993 May;122(2):115–122. doi: 10.1007/BF01103609. [DOI] [PubMed] [Google Scholar]
  18. Hoy J., Hsu K. C., Rolston K., Hopfer R. L., Luna M., Bodey G. P. Trichosporon beigelii infection: a review. Rev Infect Dis. 1986 Nov-Dec;8(6):959–967. [PubMed] [Google Scholar]
  19. Hsu N., Young L. S., Bermudez L. E. Response to stimulation with recombinant cytokines and synthesis of cytokines by murine intestinal macrophages infected with the Mycobacterium avium complex. Infect Immun. 1995 Feb;63(2):528–533. doi: 10.1128/iai.63.2.528-533.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ito K., Yamasaki H., Onoue K., Ando M. Experimental hypersensitivity pneumonitis in mice induced by Trichosporon cutaneum: histologic and immunologic features and effect of in vivo depletion of T cell subsets. Exp Lung Res. 1993 Nov-Dec;19(6):631–652. doi: 10.3109/01902149309064362. [DOI] [PubMed] [Google Scholar]
  21. Iyonaga K., Takeya M., Saita N., Sakamoto O., Yoshimura T., Ando M., Takahashi K. Monocyte chemoattractant protein-1 in idiopathic pulmonary fibrosis and other interstitial lung diseases. Hum Pathol. 1994 May;25(5):455–463. doi: 10.1016/0046-8177(94)90117-1. [DOI] [PubMed] [Google Scholar]
  22. Kemker B. J., Lehmann P. F., Lee J. W., Walsh T. J. Distinction of deep versus superficial clinical and nonclinical isolates of Trichosporon beigelii by isoenzymes and restriction fragment length polymorphisms of rDNA generated by polymerase chain reaction. J Clin Microbiol. 1991 Aug;29(8):1677–1683. doi: 10.1128/jcm.29.8.1677-1683.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kiehn T. E., Edwards F. F., Armstrong D. The prevalence of yeasts in clinical specimens from cancer patients. Am J Clin Pathol. 1980 Apr;73(4):518–521. doi: 10.1093/ajcp/73.4.518. [DOI] [PubMed] [Google Scholar]
  24. Kitabayashi A., Hirokawa M., Hatano Y., Lee M., Kuroki J., Niitsu H., Miura A. B. Granulocyte colony-stimulating factor downregulates allogeneic immune responses by posttranscriptional inhibition of tumor necrosis factor-alpha production. Blood. 1995 Sep 15;86(6):2220–2227. [PubMed] [Google Scholar]
  25. Lieschke G. J., Burgess A. W. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (1). N Engl J Med. 1992 Jul 2;327(1):28–35. doi: 10.1056/NEJM199207023270106. [DOI] [PubMed] [Google Scholar]
  26. Louie A., Baltch A. L., Smith R. P., Franke M. A., Ritz W. J., Singh J. K., Gordon M. A. Tumor necrosis factor alpha has a protective role in a murine model of systemic candidiasis. Infect Immun. 1994 Jul;62(7):2761–2772. doi: 10.1128/iai.62.7.2761-2772.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lyman C. A., Garrett K. F., Pizzo P. A., Walsh T. J. Response of human polymorphonuclear leukocytes and monocytes to Trichosporon beigelii: host defense against an emerging opportunistic pathogen. J Infect Dis. 1994 Dec;170(6):1557–1565. doi: 10.1093/infdis/170.6.1557. [DOI] [PubMed] [Google Scholar]
  28. Lyman C. A., Walsh T. J. Phagocytosis of medically important yeasts by polymorphonuclear leukocytes. Infect Immun. 1994 Apr;62(4):1489–1493. doi: 10.1128/iai.62.4.1489-1493.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Marks J. D., Marks C. B., Luce J. M., Montgomery A. B., Turner J., Metz C. A., Murray J. F. Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration. Am Rev Respir Dis. 1990 Jan;141(1):94–97. doi: 10.1164/ajrccm/141.1.94. [DOI] [PubMed] [Google Scholar]
  30. Nagai H., Guo J., Choi H., Kurup V. Interferon-gamma and tumor necrosis factor-alpha protect mice from invasive aspergillosis. J Infect Dis. 1995 Dec;172(6):1554–1560. doi: 10.1093/infdis/172.6.1554. [DOI] [PubMed] [Google Scholar]
  31. Natanson C., Hoffman W. D., Suffredini A. F., Eichacker P. Q., Danner R. L. Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann Intern Med. 1994 May 1;120(9):771–783. doi: 10.7326/0003-4819-120-9-199405010-00009. [DOI] [PubMed] [Google Scholar]
  32. Nishiura Y., Nakagawa-Yoshida K., Suga M., Shinoda T., Guého E., Ando M. Assignment and serotyping of Trichosporon species: the causative agents of summer-type hypersensitivity pneumonitis. J Med Vet Mycol. 1997 Jan-Feb;35(1):45–52. doi: 10.1080/02681219780000861. [DOI] [PubMed] [Google Scholar]
  33. Ogle C. K., Wu J. Z., Mao X., Szczur K., Alexander J. W., Ogle J. D. Heterogeneity of Kupffer cells and splenic, alveolar, and peritoneal macrophages for the production of TNF, IL-1, and IL-6. Inflammation. 1994 Oct;18(5):511–523. doi: 10.1007/BF01560698. [DOI] [PubMed] [Google Scholar]
  34. Pfaller M., Wenzel R. Impact of the changing epidemiology of fungal infections in the 1990s. Eur J Clin Microbiol Infect Dis. 1992 Apr;11(4):287–291. doi: 10.1007/BF01962067. [DOI] [PubMed] [Google Scholar]
  35. Polak-Wyss A. Protective effect of human granulocyte colony-stimulating factor (hG-CSF) on Cryptococcus and Aspergillus infections in normal and immunosuppressed mice. Mycoses. 1991 May-Jun;34(5-6):205–215. doi: 10.1111/j.1439-0507.1991.tb00645.x. [DOI] [PubMed] [Google Scholar]
  36. Rabinovici R., Feuerstein G., Abdullah F., Whiteford M., Borboroglu P., Sheikh E., Phillip D. R., Ovadia P., Bobroski L., Bagasra O. Locally produced tumor necrosis factor-alpha mediates interleukin-2-induced lung injury. Circ Res. 1996 Feb;78(2):329–336. doi: 10.1161/01.res.78.2.329. [DOI] [PubMed] [Google Scholar]
  37. Rogy M. A., Auffenberg T., Espat N. J., Philip R., Remick D., Wollenberg G. K., Copeland E. M., 3rd, Moldawer L. L. Human tumor necrosis factor receptor (p55) and interleukin 10 gene transfer in the mouse reduces mortality to lethal endotoxemia and also attenuates local inflammatory responses. J Exp Med. 1995 Jun 1;181(6):2289–2293. doi: 10.1084/jem.181.6.2289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Roilides E., Uhlig K., Venzon D., Pizzo P. A., Walsh T. J. Prevention of corticosteroid-induced suppression of human polymorphonuclear leukocyte-induced damage of Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon. Infect Immun. 1993 Nov;61(11):4870–4877. doi: 10.1128/iai.61.11.4870-4877.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Roilides E., Walsh T. J., Pizzo P. A., Rubin M. Granulocyte colony-stimulating factor enhances the phagocytic and bactericidal activity of normal and defective human neutrophils. J Infect Dis. 1991 Mar;163(3):579–583. doi: 10.1093/infdis/163.3.579. [DOI] [PubMed] [Google Scholar]
  40. Rowe J. M., Andersen J. W., Mazza J. J., Bennett J. M., Paietta E., Hayes F. A., Oette D., Cassileth P. A., Stadtmauer E. A., Wiernik P. H. A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood. 1995 Jul 15;86(2):457–462. [PubMed] [Google Scholar]
  41. Smith J. G., Magee D. M., Williams D. M., Graybill J. R. Tumor necrosis factor-alpha plays a role in host defense against Histoplasma capsulatum. J Infect Dis. 1990 Dec;162(6):1349–1353. doi: 10.1093/infdis/162.6.1349. [DOI] [PubMed] [Google Scholar]
  42. Stehle B., Weiss C., Ho A. D., Hunstein W. Serum levels of tumor necrosis factor alpha in patients treated with granulocyte-macrophage colony-stimulating factor. Blood. 1990 May 1;75(9):1895–1896. [PubMed] [Google Scholar]
  43. Steinshamn S., Waage A. Tumor necrosis factor and interleukin-6 in Candida albicans infection in normal and granulocytopenic mice. Infect Immun. 1992 Oct;60(10):4003–4008. doi: 10.1128/iai.60.10.4003-4008.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Stephens K. E., Ishizaka A., Larrick J. W., Raffin T. A. Tumor necrosis factor causes increased pulmonary permeability and edema. Comparison to septic acute lung injury. Am Rev Respir Dis. 1988 Jun;137(6):1364–1370. doi: 10.1164/ajrccm/137.6.1364. [DOI] [PubMed] [Google Scholar]
  45. Sugita T., Nishikawa A., Shinoda T., Kume H. Taxonomic position of deep-seated, mucosa-associated, and superficial isolates of Trichosporon cutaneum from trichosporonosis patients. J Clin Microbiol. 1995 May;33(5):1368–1370. doi: 10.1128/jcm.33.5.1368-1370.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Suter P. M., Suter S., Girardin E., Roux-Lombard P., Grau G. E., Dayer J. M. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis. 1992 May;145(5):1016–1022. doi: 10.1164/ajrccm/145.5.1016. [DOI] [PubMed] [Google Scholar]
  47. Teti G., Mancuso G., Tomasello F. Cytokine appearance and effects of anti-tumor necrosis factor alpha antibodies in a neonatal rat model of group B streptococcal infection. Infect Immun. 1993 Jan;61(1):227–235. doi: 10.1128/iai.61.1.227-235.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Walsh T. J., Lee J. W., Melcher G. P., Navarro E., Bacher J., Callender D., Reed K. D., Wu T., Lopez-Berestein G., Pizzo P. A. Experimental Trichosporon infection in persistently granulocytopenic rabbits: implications for pathogenesis, diagnosis, and treatment of an emerging opportunistic mycosis. J Infect Dis. 1992 Jul;166(1):121–133. doi: 10.1093/infdis/166.1.121. [DOI] [PubMed] [Google Scholar]
  49. Walsh T. J., Melcher G. P., Rinaldi M. G., Lecciones J., McGough D. A., Kelly P., Lee J., Callender D., Rubin M., Pizzo P. A. Trichosporon beigelii, an emerging pathogen resistant to amphotericin B. J Clin Microbiol. 1990 Jul;28(7):1616–1622. doi: 10.1128/jcm.28.7.1616-1622.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Walsh T. J., Newman K. R., Moody M., Wharton R. C., Wade J. C. Trichosporonosis in patients with neoplastic disease. Medicine (Baltimore) 1986 Jul;65(4):268–279. doi: 10.1097/00005792-198607000-00005. [DOI] [PubMed] [Google Scholar]
  51. Windsor A. C., Mullen P. G., Walsh C. J., Fisher B. J., Blocher C. R., Jesmok G., Fowler A. A., 3rd, Sugerman H. J. Delayed tumor necrosis factor alpha blockade attenuates pulmonary dysfunction and metabolic acidosis associated with experimental gram-negative sepsis. Arch Surg. 1994 Jan;129(1):80–89. doi: 10.1001/archsurg.1994.01420250092012. [DOI] [PubMed] [Google Scholar]
  52. Wu-Hsieh B. A., Lee G. S., Franco M., Hofman F. M. Early activation of splenic macrophages by tumor necrosis factor alpha is important in determining the outcome of experimental histoplasmosis in mice. Infect Immun. 1992 Oct;60(10):4230–4238. doi: 10.1128/iai.60.10.4230-4238.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES