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Reduced Nitric Oxide Synthase 2 (NOS2) Promoter Activity in the Syrian Hamster Renders the Animal Functionally Deficient in NOS2 Activity and Unable to Control an Intracellular Pathogen¹

Luis E. Perez^*,, Bysani Chandrasekar^*,, Omar A. Saldarriaga^,, Weiguo Zhao^*,, Lourdes T. Arteaga^*,, Bruno L. Travi and Peter C. Melby^2,*,,

^* Research Service, Department of Veterans Affairs Medical Center, South Texas Veterans Health Care System, San Antonio, TX 78229; Departments of Medicine and Microbiology and Immunology, University of Texas Health Science Center, San Antonio, TX 78229; and Centro Internacional de Entrenamiento e Investigaciones Medicas, Cali, Colombia

Progressive disease in the hamster model of visceral leishmaniasis, caused by Leishmania donovani, in contrast to infection in mice, mimics the progressive disease observed in untreated humans. During progressive infection in hamsters, there was a vigorous type 1 cellular immune response, which is typically associated with control of infection, suggesting that there was ineffective IFN--mediated macrophage activation. Indeed, at the site of infection, hamsters did not express NO synthase 2 (NOS2), which is the primary mechanism for control of infection in mice. Furthermore, in striking contrast to mouse macrophages, IFN--activated hamster macrophages did not did not express NOS2 nor generate NO, and were unable to restrict the replication of intracellular L. donovani. The absent hamster NOS2 expression was not the result of NOS2 gene deletion and the NOS2 cDNA had an intact open reading frame. Furthermore, the impaired transcription of NOS2 mRNA was selective and not due to global impairment of IFN- signaling (members of the IFN--signaling pathway were expressed and functional and IFN- up-regulated several primary and secondary response genes). Strikingly, the proximal hamster NOS2 promoter, like the human ortholog, had >20-fold less basal and IFN-/LPS-inducible activity than the corresponding mouse promoter. Thus, reduced basal and IFN--induced activity of the hamster NOS2 transcriptional unit, which is unique to this small animal and similar to the human counterpart, accompanies the inability of the animal to control an intracellular pathogen.

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