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Infection and Immunity, January 2000, p. 288-293, Vol. 68, No. 1
Department of Medicine, Weill Medical College
of Cornell University, New York, New York 10021
Received 4 June 1999/Returned for modification 5 August
1999/Accepted 11 October 1999
In experimental visceral leishmaniasis, in which the tissue
macrophage is the target, in vivo responsiveness to conventional chemotherapy (pentavalent antimony [Sb]) requires a T-cell-dependent mechanism. To determine if this mechanism involves gamma interferon (IFN-
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Copyright © 2000, American Society for Microbiology. All rights reserved.
Roles of Endogenous Gamma Interferon and Macrophage
Microbicidal Mechanisms in Host Response to Chemotherapy in
Experimental Visceral Leishmaniasis
)-induced activation and/or specific IFN-
-regulated
macrophage leishmanicidal mechanisms (generation of reactive nitrogen
or oxygen intermediates, we treated gene-deficient mice infected with
Leishmania donovani. In IFN-
gene knockout (GKO) mice,
Sb inhibited but did not kill intracellular L. donovani
(2% killing versus 76% in controls). Sb was active (>94% killing),
however, in both inducible nitric oxide synthase (iNOS) knockout (KO)
and respiratory burst (phagocyte oxidase)-deficient chronic
granulomatous disease (X-CGD) mice. Sb's efficacy was also maintained
in doubly deficient animals (X-CGD mice treated with an iNOS
inhibitor). In contrast to Sb, amphotericin B (AmB) induced high-level
killing in GKO mice; AmB was also fully active in iNOS KO and X-CGD
animals. Although resolution of L. donovani infection
requires iNOS, residual visceral infection remained largely suppressed
in iNOS KO mice treated with Sb or AmB. These results indicate that
endogenous IFN-
regulates the leishmanicidal response to Sb and
achieves this effect via a pathway unrelated to the macrophage's
primary microbicidal mechanisms. The role of IFN-
is selective,
since it is not a cofactor in the response to AmB. Treatment with
either Sb or AmB permits an iNOS-independent mechanism to emerge and control residual intracellular L. donovani infection.
*
Corresponding author. Mailing address: Box 130, 1300 York Ave., New York, NY 10021. Phone: (212) 746-6330. Fax: (212)
746-6332. E-mail: hwmurray{at}mail.med.cornell.edu.
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