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

• DOI: 10.1371/journal.ppat.1002417
• Publication Date: 2012-01-19T21:58:01Z
• Authors: E. Yaneth Osorio; Weiguo Zhao; Claudia Espitia; Omar Saldarriaga; Leo Hawel; Craig V. Byus; Bruno L. Travi; Peter C. Melby
• Keywords: STAT6; Mesocricetus

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