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TLR9 and MyD88 are crucial for the maturation and activation of dendritic cells by paromomycin-miltefosine combination therapy in visceral leishmaniasis.


ABSTRACT: BACKGROUND AND PURPOSE: The combination of paromomycin-miltefosine is a successful anti-leishmanial therapy in visceral leishmaniasis (VL). This encouraged us to study its effect on Toll-like receptor (TLR)-mediated immunomodulation of dendritic cells (DC), as DC maturation and activation is crucial for anti-leishmanial activity. EXPERIMENTAL APPROACH: In silico protein-ligand interaction and biophysical characterization of TLR9-drug interaction was performed. Interaction assays of HEK293 cells with different concentrations of miltefosine and/or paromomycin were performed, and NF-?B promoter activity measured. The role of TLR9 and MyD88 in paromomycin/miltefosine-induced maturation and activation of DCs was evaluated through RNA interference techniques. The effect of drugs on DCs was measured in terms of counter-regulatory production of IL-12 over IL-10, and characterized by chromatin immunoprecipitation assay at the molecular level. KEY RESULTS: Computational and biophysical studies revealed that paromomycin/miltefosine interact with TLR9. Both drugs, as a monotherapy/combination, induced TLR9-dependent NF-?B promoter activity through MyD88. Moreover, the drug combination induced TLR9/MyD88-dependent functional maturation of DCs, evident as an up-regulation of co-stimulatory markers, enhanced antigen presentation by increasing MHC II expression, and increased stimulation of naive T-cells to produce IFN-?. Both drugs, by modifying histone H3 at the promoter level, increased the release of IL-12, but down-regulated IL-10 in a TLR9-dependent manner. CONCLUSIONS AND IMPLICATIONS: These results provide the first evidence that the combination of paromomycin-miltefosine critically modifies the maturation, activation and development of host DCs through a mechanism dependent on TLR9 and MyD88. This has implications for evaluating the success of other combination anti-leishmanial therapies that act by targeting host DCs.

PROVIDER: S-EPMC3952803 | BioStudies |

REPOSITORIES: biostudies

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