Abstract
An important NK-cell inhibition with reduced TNF-α, IFN-γ and TLR2 expression had previously been identified in patients with diffuse cutaneous leishmaniasis (DCL) infected with Leishmania mexicana. In an attempt to pinpoint alterations in the signaling pathways responsible for the NK-cell dysfunction in patients with DCL, this study aimed at identifying differences in the NK-cell response towards Leishmania mexicana lipophosphoglycan (LPG) between patients with localized and diffuse cutaneous leishmaniasis through gene expression profiling. Our results indicate that important genes involved in the innate immune response to Leishmania are down-regulated in NK cells from DCL patients, particularly TLR and JAK/STAT signaling pathways. This down-regulation showed to be independent of LPG stimulation. The study sheds new light for understanding the mechanisms that undermine the correct effector functions of NK cells in patients with diffuse cutaneous leishmaniasis contributing to a better understanding of the pathobiology of leishmaniasis.
Highlights
Leishmania mexicana can cause two forms of clinical diseases: a benign localized cutaneous leishmaniasis (LCL) characterized by ulcers at sites of parasite inoculation, and the highly destructive and invasive form, diffuse cutaneous leishmaniasis (DCL) characterized by intensely parasitized macrophages within nodules that spread uncontrolledly throughout the skin
Patients with localized cutaneous leishmaniasis contain the parasite within granulomas, whereas patients with diffuse cutaneous leishmaniasis show uncontrolled parasite spread
Results from our study show that DCL patients suffered from reduced numbers of NK cells in blood and tissue lesions, and, that their functional capacity was markedly diminished showing a reduced production of IFN-γ and TNF-α when stimulated with Leishmania LPG [6]
Summary
Leishmania mexicana can cause two forms of clinical diseases: a benign localized cutaneous leishmaniasis (LCL) characterized by ulcers at sites of parasite inoculation, and the highly destructive and invasive form, diffuse cutaneous leishmaniasis (DCL) characterized by intensely parasitized macrophages within nodules that spread uncontrolledly throughout the skin This aggressive form invades the oropharyngeal and nasal mucosae of patients in an advanced stage of the disease. Previous work in our lab showed that NK cells are activated by Leishmania lipophosphoglycan (LPG) through TLR2 receptors inducing IFN-γ and TNF-α production [1] Another approach considered by our group was to analyze whether the cause of disease progression in DCL patients was related to an altered NK-cell response
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