Diffuse cutaneous leishmaniasis (DCL) is a rare clinical manifestation of tegumentary leishmaniasis. The molecular mechanisms underlying DCL pathogenesis remain unclear, and there is no efficient treatment available. This study investigated the systemic and in situ expression of the inflammatory response that might contribute to suppression in DCL. The plasma levels of arginase I, ornithine decarboxylase (ODC), transforming growth factor β (TGF-β), and prostaglandin E2 (PGE2) were higher in patients with DCL, compared with patients with localized cutaneous leishmaniasis (LCL) or with controls from an area of endemicity. In situ transcriptomic analyses reinforced the association between arginase I expression and enzymes involved in prostaglandin and polyamine synthesis. Immunohistochemistry confirmed that arginase I, ODC, and cyclooxygenase2 expression was higher in lesion biopsy specimens from patients with DCL than in those from patients with LCL. Inhibition of arginase I or ODC abrogates L. amazonensis replication in infected human macrophages. Our data implicate arginase I, ODC, PGE2, and TGF-β in the failure to mount an efficient immune response and suggest perspectives in the development of new strategies for therapeutic intervention for patients with DCL.
Unfettered inflammation is thought to play critical role in the development of different clinical forms of tegumentary leishmaniasis. Eicosanoids are potent mediators of inflammation and tightly associated with modulation of immune responses. In this cross-sectional exploratory study, we addressed whether targets from the eicosanoid biosynthetic pathway, assessed by multiplexed expression assays in lesion biopsy and plasma specimens, could highlight a distinct biosignature in patients with mucocutaneous leishmaniasis (MCL) or localized cutaneous leishmaniasis (LCL). Differences in immunopathogenesis between MCL and LCL may result from an imbalance between prostaglandins and leukotrienes, which may serve as targets for future host-directed therapies.
In the doses and schemes used in this study, co-administration of oral tamoxifen and Sb resulted in higher cure rates in comparison with the standard scheme of treatment, although not to statistically significant levels.
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