Subversion mechanisms by which Leishmania parasites can escape the host immune response: a signaling point of view

Abstract

The obligate intracellular parasite Leishmania must survive the antimicrobial activities of its host cell, the macrophage, and prevent activation of an effective immune response. In order to do this, it has developed numerous highly successful strategies for manipulating activities, including antigen presentation, nitric oxide and oxygen radical generation, and cytokine production. This is generally the result of interactions between Leishmania cell surface molecules, particularly gp63 and LPG, and less well identified macrophage surface receptors, causing the distortion of specific intracellular signaling cascades. We describe some of the signaling pathways and intermediates that are repressed in infected cells, including JAK/STAT, Ca(2+)-dependent protein kinase C (PKC) isoforms, and mitogen-activated protein kinases (especially ERK1/2), and proteasome-mediated transcription factor degradation. We also discuss protein tyrosine phosphatases (particularly SHP-1), intracellular Ca2+, Ca(2+)-independent PKC, ceramide, and the suppressors of cytokine signaling family of repressors, which are all reported to be activated following infection, and the role of parasite-secreted cysteine proteases.

FIG. 1.

Signaling events leading to the induction or inhibition of macrophage functions during Leishmania infection. Leishmania internalization within the macrophage is a receptor-mediated event, and this initial host-pathogen interaction is responsible for the rapid activation and deactivation of several signaling pathways leading to macrophage functions (e.g., phagocytosis, chemokine secretion, and prostaglandin secretion). SHP-1 negatively affects JAK2, Erk1/Erk2 MAP kinases, NF-κB, IRF-1, and AP-1, thus inhibiting IFN-γ-inducible macrophage functions (e.g., nitric oxide, IL-12 production, and immunoproteasome formation). STAT1α degradation by proteasome is PKCα dependent. Other phosphatases (e.g., IP₃ phosphatase and calcineurin) and surface parasite molecules (e.g., LPG) play a pivotal role in the alteration of various second messengers (e.g., PKC, Ca²⁺, inositol lipids, and inositol phosphates), regulating important phagocyte functions (e.g., NO and superoxide production). Mφ, macrophage; DAG, diacyl glycerol; PLC, phospholipase C; fMLPR, formyl peptide receptor; PIP2, phosphatidyl inositol 4,5-biphosphate.

FIG. 2.

Activation of SHP-1 in Leishmania-infected macrophages. Naive macrophages or macrophages infected for 30 min with L. donovani were stained with propidium iodide (PI) (red) or antibody specific for SHP-1 (green). SHP-1 is spread evenly throughout the cytoplasm in control cells but adopts a more punctate distribution following infection. Foci of SHP-1 are also visible in the nuclei of infected cells. Nil, no infection; Ld, L. donovani infection.