Signals and signal transduction pathways in Entamoeba histolytica during the life cycle and when interacting with bacteria or human cells

Abstract

Entamoeba histolytica is the etiological agent of amebiasis in humans. This ameba parasite resides as a commensal in the intestine where it shares intestinal resources with the bacterial microbiome. In the intestinal ecosystem, the ameba encysts and eventually develops disease by invading the tissues. E. histolytica possesses cell surface receptors for the proper sensing of signals involved in encystation or sustaining parasite interaction with bacteria and human cells. Among those receptors are the Gal/GalNAc lectin, G protein‐coupled receptors, and transmembrane kinases. In addition there are recently discovered, promising proteins, including orthologs of Toll‐type receptors and β trefoil lectins. These proteins trigger a wide variety of signal transduction pathways; however, most of the players involved in the signaling pathways evoked in this parasite are unknown. This review provides an overview of amoebic receptors and their role in encystation, adherence to bacteria or human cells, as well as the reported intracellular signal transduction processes that they can trigger. This knowledge is essential for understanding the lifestyle of E. histolytica and its cytopathic effect on bacteria and human cells that are responsible for infection.

Pathogenicity and virulence of Entamoeba histolytica , the agent of amoebiasis

“…Gradual dehydration induces the decrease in cytoplasmic volume by approximately 80% leading to retraction of the cytoplasm from the cyst wall, glycogen accumulation, and maturation of cysts by addition of the wall elements [ 22 ] such as chitin-rich microfibrils that are associated with the lectins Jacob and Jessie. The main biochemical and molecular features of Entamoeba encystation have been reviewed [ 18 , 24 ]. Clearly, changes in the environment such as starvation of the carbon source or osmotic shock induces encystation.…”

“…Several lectins from E. histolytica are potential candidates for trophozoite aggregation, including a protein recognizing oligosaccharides found in ovalbumin [ 77 ], β trefoil lectin [ 78 ], and galactose/N-acetyl galactosamine lectin (Gal/GalNAc lectin) which recognizes Gal and N-acetyl galactosamine [ 79 , 80 ]. The molecular mechanism and signalling pathways implicating these lectins in encystation are far from determined; in particular, the Gal/GalNAc lectin is a versatile receptor activating multiple overlapping signalling pathways depending on the cellular function to be performed [ 18 ]. Nevertheless, encystation signalling pathways may occur through changes in the actin-rich cytoskeleton including reduction in actin levels that lead to rounded quiescent cells [ 81 ] or disruption of actin polymerization dynamics [ 82 ]; moreover, the carboxyl terminal domain of the Gal/GalNAc lectin heavy chain interacts with the cytoskeleton [ 18 ] triggering the activation of the above-described transcription factors involved in encystation.…”

“…The molecular mechanism and signalling pathways implicating these lectins in encystation are far from determined; in particular, the Gal/GalNAc lectin is a versatile receptor activating multiple overlapping signalling pathways depending on the cellular function to be performed [ 18 ]. Nevertheless, encystation signalling pathways may occur through changes in the actin-rich cytoskeleton including reduction in actin levels that lead to rounded quiescent cells [ 81 ] or disruption of actin polymerization dynamics [ 82 ]; moreover, the carboxyl terminal domain of the Gal/GalNAc lectin heavy chain interacts with the cytoskeleton [ 18 ] triggering the activation of the above-described transcription factors involved in encystation. Recent data reinforce this hypothesis; aggregation occurs as an independent step leading eventually to encystation since the ERM-BP transcription factor participates in MGC formation in E. invadens , but silencing ERM-BP has no effect on the aggregation process [ 29 ]; indicating that trophozoite aggregation follows specific molecular regulation independent of MGC formation.…”

“…In the early stages of intestinal invasion [ 148 ], once the protective mucus layer has been destroyed, virulent trophozoites penetrate the intestinal parenchyma, adhere and destroy the extracellular matrix (ECM) through the action of amoebic surface receptors recognizing ECM components and proteinase activities [ 149 ]. The trophozoite evolves in the colon epithelium by attaching to the mammalian cell by means of surface glycosylated components like the Gal-GalNAc lectin and the glycocalyx-bound lipopeptidophosphoglycan (LPPG) [ 18 ]; or by direct amoeba-cell contact involving proteins like KERP1, KERP2 [ 150 ]; serine, threonine-, and isoleucine-rich proteins STIRPs [ 151 ] and the adhesin ADH112 [ 152 ]. Cell-cell junctions of epithelial cells are disrupted by proteinases [ 153 ], mammalian cell killing, and phagocytosis occurs; alternatively, after attaching to host cells, amoebae “chew off” and ingest host cell fragments by trogocytosis [ 154 , 155 ].…”

“…The data demonstrates that the destruction of mammalian cells requires contact with trophozoite that trigger calcium influx. Adhesion of trophozoites to enterocytes occurs via various factors on the amoebic surface, including LPPG, Gal-GalNAc lectin, KERP1, STIRP, and the CPAHD112 complex [ 18 ]; the contact led to the death of human cells in large proportions; approximately 40% of cultured enterocyte-like cells are killed within 30 minutes of interaction [ 150 , 176 ]. Dead cells can be ingested by phagocytosis, which is an important process for clearance of pathogens, necrotic or apoptotic cells [ 177 ].…”