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PLoS Pathog. Jan 2012; 8(1): e1002417.
Published online Jan 19, 2012. doi:  10.1371/journal.ppat.1002417
PMCID: PMC3261917

Progressive Visceral Leishmaniasis Is Driven by Dominant Parasite-induced STAT6 Activation and STAT6-dependent Host Arginase 1 Expression

Martin Olivier, Editor

Abstract

The clinicopathological features of the hamster model of visceral leishmaniasis (VL) closely mimic active human disease. Studies in humans and hamsters indicate that the inability to control parasite replication in VL could be related to ineffective classical macrophage activation. Therefore, we hypothesized that the pathogenesis of VL might be driven by a program of alternative macrophage activation. Indeed, the infected hamster spleen showed low NOS2 but high arg1 enzyme activity and protein and mRNA expression (p<0.001) and increased polyamine synthesis (p<0.05). Increased arginase activity was also evident in macrophages isolated from the spleens of infected hamsters (p<0.05), and arg1 expression was induced by L. donovani in primary hamster peritoneal macrophages (p<0.001) and fibroblasts (p<0.01), and in a hamster fibroblast cell line (p<0.05), without synthesis of endogenous IL-4 or IL-13 or exposure to exogenous cytokines. miRNAi-mediated selective knockdown of hamster arginase 1 (arg1) in BHK cells led to increased generation of nitric oxide and reduced parasite burden (p<0.005). Since many of the genes involved in alternative macrophage activation are regulated by Signal Transducer and Activator of Transcription-6 (STAT6), and because the parasite-induced expression of arg1 occurred in the absence of exogenous IL-4, we considered the possibility that L. donovani was directly activating STAT6. Indeed, exposure of hamster fibroblasts or macrophages to L. donovani resulted in dose-dependent STAT6 activation, even without the addition of exogenous cytokines. Knockdown of hamster STAT6 in BHK cells with miRNAi resulted in reduced arg1 mRNA expression and enhanced control of parasite replication (p<0.0001). Collectively these data indicate that L. donovani infection induces macrophage STAT6 activation and STAT6-dependent arg1 expression, which do not require but are amplified by type 2 cytokines, and which contribute to impaired control of infection.

Author Summary

Visceral leishmaniasis (VL), caused by the intracellular protozoan Leishmania donovani, is a progressive, potentially fatal infection found in many resource-poor regions of the world. We initiated these studies of an experimental model of VL to better understand the molecular and cellular determinants underlying this disease. We found that host macrophages or fibroblasts, when infected with Leishmania donovani or exposed to products secreted by the parasite, are permissive to infection because they fail to metabolize arginine to generate nitric oxide, the effector molecule needed to kill the intracellular parasites. Instead, the infected host cells are activated in a way that leads to the expression of arginase, an enzyme that metabolizes arginine to produce polyamines, which support parasite growth. This detrimental activation pathway was dependent on the parasite-induced activation of the transcription factor STAT6, but contrary to the previously accepted paradigm, did not require (but was amplified by) the presence of polarized Th2 cells or type 2 cytokines. Knockdown of host arginase or STAT6 enhanced control of the infection, indicating that this activation pathway has a critical role in the pathogenesis of the disease. Interventions designed to inhibit the STAT6-arginase-polyamine pathway could help in the treatment or prevention of VL.


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