The role of lipopeptidophosphoglycan in the immune response to Entamoeba histolytica

Abstract

The sensing of Pathogen Associated Molecular Patterns (PAMPs) by innate immune receptors, such as Toll-like receptors (TLRs), is the first step in the inflammatory response to pathogens. Entamoeba histolytica, the etiological agent of amebiasis, has a surface molecule with the characteristics of a PAMP. This molecule, which was termed lipopeptidophosphoglycan (LPPG), is recognized through TLR2 and TLR4 and leads to the release of cytokines from human monocytes, macrophages, and dendritic cells; LPPG-activated dendritic cells have increased expression of costimulatory molecules. LPPG activates NKT cells in a CD1d-dependent manner, and this interaction limits amebic liver abscess development. LPPG also induces antibody production, and anti-LPPG antibodies prevent disease development in animal models of amebiasis. Because LPPG is recognized by both the innate and the adaptive immune system (it is a "Pamptigen"), it may be a good candidate to develop a vaccine against E. histolytica infection and an effective adjuvant.

Figure 1

(a) Lipopolysaccharide (LPS) from the Gram-negative bacterium Escherichia coli is the most potent activator of TLR4 [54]. (b) Alpha-galactosyl ceramide from the marine sponge Agelas mauritanius is presented via CD1d and activates NKT cells [55]. (c) Partial structure of lipopeptidophosphoglycan (LPPG) from Entamoeba histolytica of the HM1 : IMSS strain, which was originally isolated from a patient with liver abscess [56, 57]. The structure of the active phosphoinositol moiety of LPPG was characterized in [58].

Figure 2

The role of lipopeptidophosphoglycan (LPPG) in the immune response to Entamoeba histolytica. During E. histolytica infection, amebic enzymes and enzymes and reactive oxygen species from neutrophils cause tissue damage. LPPG released from lysed trophozoites is recognized through TLR2 and TLR4/CD14 and induces the production of IL-8, IL-10, IL-12p40, and TNF-alpha by monocytes [85, 96]. Macrophages and dendritic cells internalize LPPG into LAMP-1+ endosomes, and LPPG-activated dendritic cells have increased expression of costimulatory molecules CD80, CD86, and CD40 and produce TNF-alpha, IL-8, and IL-12 [97]. NKT cells are also activated by LPPG, and this depends on the presence of CD1d on dendritic cells and simultaneous TLR2 and TLR6 signaling [58]. Anti-LPPG antibodies have been described in humans and in animal models [–53]. The mechanism that leads to the production of these antibodies has not been determined, but it is probably influenced by the innate signaling of LPPG on dendritic cells and B cells.