Manipulation of macrophage signaling by Leishmania virulence factors.

Leishmania, a macrophage-residing parasite, expresses virulence factors that intercept macrophage signaling and inflicts leishmaniasis. Recently described virulence factors- eEF-1α (eukaryotic elongation factor), LmjF_36_3850 (Leishmania major F_36_3850), LdTyrPIP_22 (LDBPK_220120.1) and LmjMAPK (L. major mitogen activated protein kinase)-4/12 selectively modulate the activities of kinases, phosphatases and metabolism of phosphatidylinositol influencing the infection outcome. LmjF_36_3850, abundant in virulent L. major, interferes with PKC (Protein kinase C) activation; OAG (1-oleoyl-2-acetyl-sn-glycerol) supplementation enhanced PKC phosphorylation, increasing IL-12, but reducing IL-10, production and increased disease-promoting T cells. LdTyrPIP_22, a dual-specificity phosphatase, dephosphorylates phosphotyrosine residues and PI(3)P/PI(4)P, within the flagellar pocket and vesicles, suggesting a role in phosphoinositide (PI) signaling during differentiation. Its L. mexicana ortholog, LmDUSP1 (Dual-specificity Phosphatase), is a virulence factor linked to infectivity. 170 PX-domain-containing proteins in Kinetoplastea are implicated in phosphoinositide-mediated signaling, transport, and membrane trafficking. This review constructs a new framework of virulence factor-modulated host cell signaling as a bi-directional host-parasite interaction.