Impact of Leishmania mexicana Infection on Dendritic Cell Signaling and Functions

Abstract

Leishmania parasites have the ability to modify macrophage signaling pathways in order to survive and multiply within its mammalian host. They are also known to invade other cells including neutrophils, fibroblasts and dendritic cells (DCs). DCs have an important role in immunity as the link between innate and adaptive immunity, necessary for the development of an effective response; however, the impact of Leishmania mexicana infection on DCs has been poorly studied. Herein, we report that Leishmania infection rapidly induced DC protein tyrosine phosphatases activity, leading to MAP kinases inactivation. In line with this, L. mexicana was found to decrease the nuclear translocation of transcription factors such as AP-1 and NF-κB. Concomitantly, L. mexicana-infected DCs showed reduced expression of several surface antigen-presenting and co-stimulatory molecules upon LPS stimulation. Leishmania-induced interference on DC maturation was further reflected by their reduced capacity to present OVA antigen to OVA-specific T cells, as shown by abrogation of IL-2 production by the T cells. Collectively, our data revealed that DC infection by L. mexicana appears to affect the cellular and immunological mechanisms necessary for the development of an effective and protective immune response, therefore favouring the survival and propagation of the parasite within its host.

Structurally optimized analogs of the retrograde trafficking inhibitor Retro-2cycl limit Leishmania infections

“…Although there isn’t a consensus on the mechanism by which inhibition of cytokine release by infected cells is achieved, some of the proposed mechanisms have implicated parasite molecules that are released from LPVs that then interfere with signal transduction intermediates [13][16]. Retro-2 cycl is known to function by disrupting Stx5 that exerts its functions in the secretory pathway.…”

Dynamic balance of pro‐ and anti‐inflammatory signals controls disease and limits pathology

“…Leishmania is a parasite that causes disease manifestation in the skin or internal organs, including the spleen and bone marrow . Macrophages are the primary host cells for Leishmania ; however, it is possible for the parasite to inhabit neutrophils, fibroblasts, and DCs …”

“…144 Macrophages are the primary host cells for Leishmania; however, it is possible for the parasite to inhabit neutrophils, fibroblasts, and DCs. 145 During progressive infection, cytokines play different roles in containment of Leishmania infection. 146 In general, parasite growth is dependent on IFNγ, as well as other inflammatory cytokines.…”

Inhibitor of serine peptidase 2 enhancesLeishmania majorsurvival in the skin through control of monocytes and monocyte‐derived cells

“…IFN-γ has been reported to induce monocyte chemotaxis (47) and is required for the differentiation of monocytes into functional TNF-α– and iNOS-producing DCs (48). An increase in IFN-γ could also account for the increase in monocyte and monocyte-derived cells at the site of Δ isp2/3 infection.…”

“…The presence of ISP2 also reduced the activation of phagocytes in the ear and was associated with reduced IFN-g and iNOS in the lesion, which suggests that ISP2 is important in limiting T h 1-associated responses. IFN-g has been reported to induce monocyte chemotaxis (47) and is required for the differentiation of monocytes into functional TNF-a-and iNOS-producing DCs (48). An increase in IFN-g could also account for the increase in monocyte and monocyte-derived cells at the site of Disp2/3 infection.…”