: Syrian hamsters recapitulate the two major forms of infection with Leishmania donovani seen in man. After systemic infection, these animals develop a progressive disease that mimics the clinical-pathological features of human VL. However, hamsters infected in the skin control the infection locally, and acquire immunity to systemic challenge, akin to sub-clinically infected individuals who develop immunity against visceral disease. These two broad features prompted us to initiate studies to dissect the molecular immunopathogenesis of L. donovani infection in this unique animal model. In preliminary studies we found that during progressive disease in the hamster model of VL, a Type 1 T cell response is mounted, but is ineffective and accompanied by undetectable NOS2 expression. Furthermore, in contrast to mouse macrophages, IFN-gamma-activated hamster macrophages do not produce detectable NO and are unable to control intracellular infection. These distinctions between hamsters and mice provide the impetus to directly compare and contrast mechanisms of macrophage activation/deactivation in these species, with particular focus on the NOS2-arginase metabolic pathways. We will extend in vitro findings to in vivo proof-of-principle studies in the hamster, again with the focus on the role of the NOS2-arginase metabolic pathways in resistance to disease and protective immunity. We will approach the role of NOS2 and arginase in infection with L donovani from two opposite, but complementary directions.
In Specific Aims 1 and 2 we will determine the role of NOS2 and arginase expression in the pathogenesis of visceral infection through in vitro studies of infected hamster and mouse macrophages, and in vivo studies of systemically infected hamsters.
Specific Aim 1 will test the hypothesis that the impaired capacity of hamster macrophages to control L. donovani infection is a result of the hypo-responsiveness of NOS2 to IFN-gamma-mediated activation, and that this NOS2 hyporesponsiveness is mediated through transcriptional mechanism(s).
Specific Aim 2 will test the hypothesis that the impaired NOS2 expression sets the stage for an arginase-dominated alternative activation or deactivation pathway in infected hamster or human macrophages, which leads to impaired parasite killing.
In Specific Aim 3 we will determine if the control of primary cutaneous infection and protection against secondary visceral challenge following acquisition of immunity is mediated by a reversal of the default toward low NOS2 and high arginase expression. We hypothesize that NOS2-independent mechanisms contribute to resistance and we will break new ground in the discovery of a gene expression profile that characterizes resistance to primary and secondary infection in the hamster. These studies in the hamster will fill a knowledge gap by defining mechanisms of disease and immunity that are strikingly different from those of the murine model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061624-03
Application #
7174817
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
2005-02-01
Project End
2010-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$295,121
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Soong, Lynn; Henard, Calvin A; Melby, Peter C (2012) Immunopathogenesis of non-healing American cutaneous leishmaniasis and progressive visceral leishmaniasis. Semin Immunopathol 34:735-51
Saldarriaga, Omar A; Travi, Bruno L; Choudhury, Goutam Ghosh et al. (2012) Identification of hamster inducible nitric oxide synthase (iNOS) promoter sequences that influence basal and inducible iNOS expression. J Leukoc Biol 92:205-18
Osorio, E Yaneth; Zhao, Weiguo; Espitia, Claudia et al. (2012) Progressive visceral leishmaniasis is driven by dominant parasite-induced STAT6 activation and STAT6-dependent host arginase 1 expression. PLoS Pathog 8:e1002417
Espitia, Claudia M; Zhao, Weiguo; Saldarriaga, Omar et al. (2010) Duplex real-time reverse transcriptase PCR to determine cytokine mRNA expression in a hamster model of New World cutaneous leishmaniasis. BMC Immunol 11:31
Osorio, Yaneth; Bonilla, Diana L; Peniche, Alex G et al. (2008) Pregnancy enhances the innate immune response in experimental cutaneous leishmaniasis through hormone-modulated nitric oxide production. J Leukoc Biol 83:1413-22
Perez, Luis E; Chandrasekar, Bysani; Saldarriaga, Omar A et al. (2006) 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 pathogen. J Immunol 176:5519-28