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,
,¶
* Department of Internal Medicine,
Department of Biochemistry,
Department of Microbiology, and
Department of Epidemiology, University of Iowa, and
¶ Veterans Affairs Medical Center, Iowa City, IA 52242;
|| Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239; and
# Department of Biochemistry and Molecular Biology, Universidad de Extremadura, Cáceres, Spain
Classical activation of macrophages infected with Leishmania species results in expression and activation of inducible NO synthase (iNOS) leading to intracellular parasite killing. Macrophages can contrastingly undergo alternative activation with increased arginase activity, metabolism of arginine along the polyamine pathway, and consequent parasite survival. An active role for parasite-encoded arginase in host microbicidal responses has not previously been documented. To test the hypothesis that parasite-encoded arginase can influence macrophage responses to intracellular Leishmania, a comparative genetic approach featuring arginase-deficient mutants of L. mexicana lacking both alleles of the gene encoding arginase (
arg), as well as wild-type and complemented arg controls (arg[pArg]), was implemented. The studies showed: 1) the absence of parasite arginase resulted in a significantly attenuated infection of mice (p < 0.05); 2) poorer survival of arg in mouse macrophages than controls correlated with greater NO generation; 3) the difference between arg or control intracellular survival was abrogated in iNOS-deficient macrophages, suggesting iNOS activity was responsible for increased arg killing; 4) consistently, immunohistochemistry showed enhanced nitrotyrosine modifications in tissues of mice infected with arg compared with control parasites. Furthermore, 5) in the face of decreased parasite survival, lymph node cells draining cutaneous lesions of arg parasites produced more IFN-
and less IL-4 and IL-10 than controls. These data intimate that parasite-encoded arginase of Leishmania mexicana subverts macrophage microbicidal activity by diverting arginine away from iNOS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI45540, AI067874, and AI048822 (to M.E.W.), AI10096 (to S.C.R.), and AI41622 (to B.U.), and a Merit Review and Persian Gulf grant from the Department of Veterans Affairs (to M.E.W.). The work was performed while U.G. served as a fellow on National Institutes of Health T32 AI07511.
2 Current address: Pacific University, School of Pharmacy, Hillsboro, OR 97123.
3 Address correspondence and reprint requests to Dr. Mary E. Wilson, University of Iowa, SW34-GH, 200 Hawkins Drive, Iowa City, IA 52242. E-mail address: mary-wilson{at}uiowa.edu
4 Abbreviations used in this paper: iNOS, inducible NO synthase; BMM, bone marrow macrophage; MOI, multiplicity of infection; MvLu, mink lung fibroblast.
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  J. M. Boitz, P. A. Yates, C. Kline, U. Gaur, M. E. Wilson, B. Ullman, and S. C. Roberts Leishmania donovani Ornithine Decarboxylase Is Indispensable for Parasite Survival in the Mammalian Host Infect. Immun., February 1, 2009; 77(2): 756 - 763. [Abstract] [Full Text] [PDF]
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