PMID- 22275864
OWN - NLM
STAT- MEDLINE
DCOM- 20140626
LR  - 20211021
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 8
IP  - 1
DP  - 2012 Jan
TI  - Progressive visceral leishmaniasis is driven by dominant parasite-induced STAT6 
      activation and STAT6-dependent host arginase 1 expression.
PG  - e1002417
LID - 10.1371/journal.ppat.1002417 [doi]
LID - e1002417
AB  - 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.
FAU - Osorio, E Yaneth
AU  - Osorio EY
AD  - Research Service, Department of Veterans Affairs Medical Center, South Texas 
      Veterans Health Care System, San Antonio, Texas, United States of America.
FAU - Zhao, Weiguo
AU  - Zhao W
FAU - Espitia, Claudia
AU  - Espitia C
FAU - Saldarriaga, Omar
AU  - Saldarriaga O
FAU - Hawel, Leo
AU  - Hawel L
FAU - Byus, Craig V
AU  - Byus CV
FAU - Travi, Bruno L
AU  - Travi BL
FAU - Melby, Peter C
AU  - Melby PC
LA  - eng
SI  - GENBANK/DQ649412
SI  - GENBANK/HM801027
SI  - GENBANK/HM801028
GR  - R01 AI061624/AI/NIAID NIH HHS/United States
GR  - AI061624/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120119
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Cytokines)
RN  - 0 (Polyamines)
RN  - 0 (STAT6 Transcription Factor)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 3.5.3.1 (Arginase)
SB  - IM
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Arginase/genetics/*metabolism
MH  - Arginine/metabolism
MH  - Base Sequence
MH  - Cricetinae
MH  - Cytokines/genetics/metabolism
MH  - Gene Expression Regulation/physiology
MH  - Host-Pathogen Interactions
MH  - Humans
MH  - Leishmania donovani/growth & development/*pathogenicity
MH  - Leishmaniasis, Visceral/enzymology/*metabolism/parasitology
MH  - Macrophage Activation
MH  - Macrophages/enzymology/immunology/metabolism
MH  - Mesocricetus
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Molecular Sequence Data
MH  - Nitric Oxide/*metabolism
MH  - Polyamines/analysis/metabolism
MH  - STAT6 Transcription Factor/genetics/*metabolism
MH  - Sequence Analysis, DNA
MH  - Spleen/cytology/metabolism
MH  - Time Factors
PMC - PMC3261917
COIS- The authors have declared that no competing interests exist.
EDAT- 2012/01/26 06:00
MHDA- 2014/06/27 06:00
PMCR- 2012/01/19
CRDT- 2012/01/26 06:00
PHST- 2011/04/19 00:00 [received]
PHST- 2011/10/19 00:00 [accepted]
PHST- 2012/01/26 06:00 [entrez]
PHST- 2012/01/26 06:00 [pubmed]
PHST- 2014/06/27 06:00 [medline]
PHST- 2012/01/19 00:00 [pmc-release]
AID - PPATHOGENS-D-11-00846 [pii]
AID - 10.1371/journal.ppat.1002417 [doi]
PST - ppublish
SO  - PLoS Pathog. 2012 Jan;8(1):e1002417. doi: 10.1371/journal.ppat.1002417. Epub 2012 
      Jan 19.