Evasion of Host Defence by Leishmania donovani: Subversion of Signaling Pathways

Figure 1

Manipulation of macrophage signaling pathways by L. donovani. L. donovani-derived molecules like EF-1α and Fructose 1,6 bisphosphate aldolase activate SHP-1 which negatively affects JAK2, STAT1, ERK1/2, and IRAK-1 inhibiting IFN-γ-induced NO production and TLR-mediated production of cytokines like IL-12, TNF-α. Impairment of IFN-γ-dependent pathway also includes reduced level of JAK2 expression and proteasome-mediated degradation of STAT1α. NF-κB-dependent pathway is blocked by impaired degradation of IκB. Other than SHP-1, L. donovani also leads to an enhanced expression of MKP3, PP2A, and MKP1 by inducing PKCζ, and PKCε respectively. These dual phosphatases or serine/threonine phsophatases inhibit p38 (MKP1) and ERK1/2 (MKP3/PP2A) resulting in upregulation of IL-10 and downregulation of NO and TNF-α production. PKC-mediated secretion of immunosuppressive molecule PGE2 is also observed. Enhanced level of endogenous ceramide inhibits PKCβ leading to an impaired oxidative burst. PKC-dependent phosphorylation of MARKS and MRP and resulting phagosomal maturation is also inhibited by the parasite. Solid lines: Interaction or positive/negative modulation; dashed lines, interrupted pathway; MyD88: myeloid differentiation primary-response gene 88; IRAK1: IL-1R-associated Kinase 1; TRAF6: TNF receptor-associated factor 6.