title: Progressive visceral leishmaniasis is driven by dominant parasite-induced STAT6 activation and STAT6-dependent host arginase 1 expression.
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.
authors.affiliation: Research Service, Department of Veterans Affairs Medical Center, South Texas Veterans Health Care System, San Antonio, Texas, United States of America.
authors.forename: E Yaneth
authors.initials: EY
authors.lastname: Osorio
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhao
authors.forename: Claudia
authors.initials: C
authors.lastname: Espitia
authors.forename: Omar
authors.initials: O
authors.lastname: Saldarriaga
authors.forename: Leo
authors.initials: L
authors.lastname: Hawel
authors.forename: Craig V
authors.initials: CV
authors.lastname: Byus
authors.forename: Bruno L
authors.initials: BL
authors.lastname: Travi
authors.forename: Peter C
authors.initials: PC
authors.lastname: Melby
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D001483:Base Sequence; D006224:Cricetinae; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007893:Leishmania donovani / Q000254:growth & development / Q000472:pathogenicity*; D007898:Leishmaniasis, Visceral / Q000201:enzymology / Q000378:metabolism* / Q000469:parasitology; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000378:metabolism*; D011073:Polyamines / Q000032:analysis / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D011073:Polyamines; D050800:STAT6 Transcription Factor; D009569:Nitric Oxide; D001120:Arginine; D001119:Arginase