Abstract
The kinetoplastid protozoan parasites belonging to the genus Leishmania are the causative agents of different clinical forms of leishmaniasis, a vector-borne infectious disease with worldwide prevalence. The protective host immune response against Leishmania parasites relies on myeloid cells such as dendritic cells and macrophages in which upon stimulation by cytokines (e.g., interferon-γ) a complex network of signaling pathways is switched on leading to strong antimicrobial activities directed against the intracellular parasite stage. The regulation of these pathways classically depends on post-translational modifications of proteins, with phosphorylation events playing a cardinal role. Leishmania parasites deactivate their phagocytic host cells by inducing specific mammalian phosphatases that are capable to impede signaling. On the other hand, there is now also evidence that Leishmania spp. themselves express phosphatases that might target host cell molecules and thereby facilitate the intracellular survival of the parasite. This review will present an overview on the modulation of host phosphatases by Leishmania parasites as well as on the known families of Leishmania phosphatases and their possible function as virulence factors. A more detailed understanding of the role of phosphatases in Leishmania–host cell interactions might open new avenues for the treatment of non-healing, progressive forms of leishmaniasis.
Highlights
Epidemiology and Disease DevelopmentLeishmaniasis is a worldwide prevalent infectious disease
In L. major-infected macrophages activated by anti-CD40, siRNA-mediated inhibition of DUSP6 led to ERK activation, enhanced production of IL-10, and reduced expression of IL-12 and iNOS, whereas inhibition of DUSP1 caused p38 activation and increased generation of IL-12 and iNOS
In vivo overexpression of DUSP6 or pharmacological inhibition of DUSP1 both ameliorated the course a cutaneous L. major infection [63]. This functional dichotomy between DUSP6 and DUSP1 has been reported in the context of macrophage coinfections with the immunomodulatory bacterium Mycobacterium indicus pranii and L. donovani
Summary
Epidemiology and Disease DevelopmentLeishmaniasis is a worldwide prevalent infectious disease. Activation of host phosphatases following Leishmania infection has been described in macrophages [43] and dendritic cells [47] and helps to explain the reduced immune response observed during visceral leishmaniasis. In L. donovani-infected macrophages activation of PP2A was triggered by host production of ceramide after parasite uptake which resulted in the dephosphorylation of AKT and the subsequent decrease of TNF secretion [50].
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