The parasite lipoprotein antigen B: a possible link between immunoregulation and lipid metabolism

Abstract

The larvae of Echinococcus granulosus s.l. (hydatid) grows in the viscera of the intermediate hosts (domestic ungulates, accidentally humans), causing a chronic infection. The hydatid is well adapted to its host since it is able to control inflammation and adquiere host lipids (cholesterol) that the parasite cannot synthesize. Antigen B (EgAgB) is a 230 kDa lipoprotein containing around 50% in mass of lipids (polar and neutral), resembling the protein/lipid ratio of HDL3. EgAgB protein moiety is encoded by five genes (EgAgB1-5) belonging to a cestode-specific family of hydrophobic ligands binding proteins of unknown function. EgAgB interferes with dendritic cell (DC) activation in vitro, but the modulatory mechanisms involved have not been elucidated. Since HDL's ability to remove cholesterol has been related to immunomodulation effects in innate cells, we hypothesize that EgAgB uptakes host cholesterol from myeloid innate cells, including DCs, contributing to regulate inflammatory activation pathways. We found that native EgAgB is bound to DCs in a TLR4 and TLR2-independent manner. When co-administered with LPS, EgAgB inhibited TLR4 dimerization and cytokine (IL6, IL12, IFN?) secretion, but not CD86 and CD40 expression in DCs. Furthermore, EgAgB inhibited LPS binding to DCs, suggesting it might neutralize LPS in the milieu as HDL3 does, contributing to their inhibitory effects. In addition, in a mixed lymphocyte reaction, EgAgB seemed to favor a Th2-type differentiation profile. On the other hand, EgAgB promoted cholesterol efflux from THP-1 macrophages similarly to HDL and HDL3. An increase of ABCA1 expression (induced by an LXR agonist) or blocking ABCA1-mediated efflux (by BLT4 inhibitor) did not affect EgAgB's ability to efflux cholesterol from macrophages, suggesting the involvement of other receptors. Further studies are needed to examine a putative relation between EgAgB's ability to efflux cholesterol and to regulate the activation of innate cells.