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Infection and Immunity, May 2000, p. 2546-2552, Vol. 68, No. 5
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 (M
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
) represents the
major cell defense against this pathogen; when activated with gamma interferon (IFN-
), murine M
s kill the fungus by an
oxygen-independent mechanism. Our goal was to determine the role of
nitric oxide in the fungicidal effect of M
s on P. brasiliensis conidia. The results revealed that IFN-
-activated
murine M
s inhibited the conidium-to-yeast transformation process in
a dose-dependent manner; maximal inhibition was observed in M
s
activated with 50 U/ml and incubated for 96 h at 37°C. When
M
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-
monoclonal antibodies. Activation by
IFN-
also enhanced M
nitric oxide production, as revealed by
increasing NO2 values (8 ± 3 µM in nonactivated
M
s versus 43 ± 13 µM in activated M
s). The neutralization
of IFN-
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-
-activated murine
M
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.
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