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Infection and Immunity, May 2000, p. 2546-2552, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Nitric Oxide Participation in the Fungicidal Mechanism of Gamma Interferon-Activated Murine Macrophages against Paracoccidioides brasiliensis Conidia

Angel Gonzalez, Waldemar de Gregori, Diana Velez, Angela Restrepo, and Luz E. Cano*

Medical and Experimental Mycology Group, Corporación para Investigaciones Biológicas, Medellín, Colombia

Received 16 August 1999/Returned for modification 22 September 1999/Accepted 26 January 2000

Paracoccidioidomycosis, a systemic mycosis restricted to Latin America and produced by the dimorphic fungus Paracoccidioides brasiliensis, is probably acquired by inhalation of conidia produced by the mycelial form. The macrophage (Mphi ) represents the major cell defense against this pathogen; when activated with gamma interferon (IFN-gamma ), murine Mphi s kill the fungus by an oxygen-independent mechanism. Our goal was to determine the role of nitric oxide in the fungicidal effect of Mphi s on P. brasiliensis conidia. The results revealed that IFN-gamma -activated murine Mphi s inhibited the conidium-to-yeast transformation process in a dose-dependent manner; maximal inhibition was observed in Mphi s activated with 50 U/ml and incubated for 96 h at 37°C. When Mphi s were activated with 150 to 200 U of cytokine per ml, the number of CFU was 70% lower than in nonactivated controls, indicating that there was a fungicidal effect. The inhibitory effect was reversed by the addition of anti-IFN-gamma monoclonal antibodies. Activation by IFN-gamma also enhanced Mphi nitric oxide production, as revealed by increasing NO2 values (8 ± 3 µM in nonactivated Mphi s versus 43 ± 13 µM in activated Mphi s). The neutralization of IFN-gamma also reversed nitric oxide production at basal levels (8 ± 5 µM). Additionally, we found that there was a significant inverse correlation (r = -0.8975) between NO2- concentration and transformation of P. brasiliensis conidia. Additionally, treatment with any of the three different nitric oxide inhibitors used (arginase, NG-monomethyl-L-arginine, and aminoguanidine), reverted the inhibition of the transformation process with 40 to 70% of intracellular yeast and significantly reduced nitric oxide production. These results show that IFN-gamma -activated murine Mphi s kill P. brasiliensis conidia through the L-arginine-nitric oxide pathway.

* Corresponding author. Mailing address: Medical and Experimental Mycology Group, Corporación para Investigaciones Biológicas (CIB), Carrera 72 A No 78 B 141, A. A. 73 78, Medellín, Colombia. Phone: 57-4-441 08 55. Fax: 57-4-441 55 14. E-mail: lula{at}epm.net.co.

Infection and Immunity, May 2000, p. 2546-2552, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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