Leishmania interferes with host cell signaling to devise a survival strategy

Abstract

The protozoan parasite Leishmania spp. exists as extracellular promastigotes in its vector whereas it resides and replicates as amastigotes within the macrophages of its mammalian host. As a survival strategy, Leishmania modulates macrophage functions directly or indirectly. The direct interference includes prevention of oxidative burst and the effector functions that lead to its elimination. The indirect effects include the antigen presentation and modulation of T cell functions in such a way that the effector T cells help the parasite survive by macrophage deactivation. Most of these direct and indirect effects are regulated by host cell receptor signaling that occurs through cycles of phosphorylation and dephosphorylation in cascades of kinases and phosphatases. This review highlights how Leishmania selectively manipulates the different signaling pathways to ensure its survival.

Figure 1

General principles of signal regulation by kinases and Phosphatases: the phosphorylation and dephosphorylation of the protein, the former being catalyzed by a kinase, and the latter by a phosphatase. Phosphorylation usually causes a conformational change in the protein.

Figure 2

Modulation of CD40 responsiveness in Leishmania-infected macrophages: crosslinking of anti-CD40 antibody activates p38 MAPK-induced leishmanicidal function via iNOS2 induction. Leishmania infection downregulates CD40-induced p38 MAPK phosphorylation and uses the capability of this receptor to signal along an ERK1/2-dependent pathway to produce the proparasitic Th2 cytokine IL-10 from macrophages. iNOS2: inducible nitric oxide synthase 2; NO: nitric oxide; PTP: Protein tyrosine phosphatases.

Figure 3

STAT1 phosphorylation regulation through IFNγ receptor: infected macrophages display reduced levels of total and phosphorylated JAK1 and JAK2 and attenuate IFN-γ induced STAT-1 phosphorylation in macrophages, aiding the parasites in escaping host immunity. GAS: Interferon gamma-activated site.

Figure 4

PKC regulation in Leishmania infected macrophages: LPG of Leishmania inhibits PKC activation and translocation to the membrane. PKC is responsible for phosphorylation of p47phox and p67phox components of NADPH oxidase which are subsequently translocated to phagosomal membrane to form NADPH oxidase complex, which is responsible for superoxide anion generation and hence parasite killing. Further PKC phosphorylates myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP) which are involved in actin turnover and finally in phagosomal maturation and lysosomal fusion resulting in parasite killing. As PKC activation is inhibited by Leishmania, this results in subsequent inhibition of all the above mentioned processes thereby favoring parasite survival.

Figure 5

MAPK phosphorylation in Leishmania-infected macrophages: Leishmania infection of macrophages represses the most important MAPK family members: ERK1/2, p38, and JNK. MAPK inactivation is accompanied by inhibition of transcription factors Elk-1, c-fos, IRF-1, AP-1, and NF-κB and IFN-γ-dependent NO generation.