Leishmania donovani: impairment of the cellular immune response against recombinant ornithine decarboxylase protein as a possible evasion strategy of Leishmania in visceral leishmaniasis
| Autor: | Anil Kumar, Vijay Mahantesh, Krishna Pandey, Pradeep Das, Ajay Amit, Anupam Yadav, Sanjiva Bimal, Rajesh Chaudhary, S. K. Singh, Vidyanand Rabidas, Shashi S. Suman, Vahab Ali, Manas Ranjan Dikhit, Arvind Singh Chandel |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Adolescent Virulence Factors Leishmania donovani Trypanothione Biology Nitric Oxide Ornithine Decarboxylase Peripheral blood mononuclear cell Microbiology Ornithine decarboxylase chemistry.chemical_compound Young Adult Immune system medicine Immune Tolerance Macrophage Humans Immune Evasion Immunity Cellular biology.organism_classification Leishmania medicine.disease Recombinant Proteins Infectious Diseases Visceral leishmaniasis chemistry Immunology Leukocytes Mononuclear Cytokines Leishmaniasis Visceral Parasitology Female |
| Zdroj: | International journal for parasitology. 45(1) |
| ISSN: | 1879-0135 |
| Popis: | Ornithine decarboxylase, the rate limiting enzyme of the polyamine biosynthesis pathway, is significant in the synthesis of trypanothione, T(SH)2, the major reduced thiol which is responsible for the modulation of the immune response and pathogenesis in visceral leishmaniasis. Data on the relationship between ornithine decarboxylase and the cellular immune response in VL patients are limited. Therefore, we purified a recombinant ornithine decarboxylase from Leishmania donovani (r-LdODC) of approximately 77 kDa and examined its effects on the immunological responses in peripheral blood mononuclear cells of human visceral leishmaniasis cases. For these studies, α-difluoromethylornithine was tested as an inhibitor and was used in parallel in all experiments. The r-LdODC was identified as having a direct correlation with parasite growth and significantly increased the number of promastigotes as well as axenic amastigotes after 96 h of culture. The stimulation of peripheral blood mononuclear cells with r-LdODC up-regulated IL-10 production but not IFN-γ production from CD4+ T cells in active as well as cured visceral leishmaniasis cases, indicating a pivotal role for r-LdODC in causing strong immune suppression in a susceptible host. In addition, severe hindrance of the immune response and anti-leishmanial macrophage function due to r-LdODC, as revealed by decreased IL-12 and nitric oxide production, and down-regulation in mean fluorescence intensities of reactive oxygen species, occurred in visceral leishmaniasis patients. There was little impact of r-LdODC in the killing of L. donovani amastigotes in macrophages of visceral leishmaniasis patients. In contrast, when cultures of promastigotes and amastigotes, and patients’ blood samples, were directed against α-difluoromethylornithine, parasite numbers significantly reduced in culture, whereas the levels of IFN-γ and IL-12, and the production of reactive oxygen species and nitric oxide, were significantly elevated. Therefore, we demonstrated cross-talk with the use of α-difluoromethylornithine which can reduce the activity of ornithine decarboxylase of L. donovani, eliminating the parasite-induced immune suppression and inducing collateral host protective responses in visceral leishmaniasis. |
| Databáze: | OpenAIRE |
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