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Infection biology

Nibbled to death

Nature volume 508, pages 462463 (24 April 2014) | Download Citation

Trogocytosis, a process in which one cell 'takes a bite' out of another, had previously been seen only in immune cells. But the phenomenon has now been found in Entamoeba histolytica, as a way for this parasite to kill host cells. See Letter p.526

Early in an immune response, antigen molecules are captured by antigen-presenting cells and displayed on the cells' surface, where they are recognized by receptors on the surface of lymphocytes (B cells, T cells and natural killer cells)1,2. The lymphocyte then becomes joined to the antigen-presenting cell and extracts these surface molecules along with patches of the cell membrane. This process, termed trogocytosis (from the Greek word trogo, to nibble)2,3, activates the lymphocyte to initiate a specific immune response to that antigen. Until now, trogocytosis had been observed only between immune cells. But in this issue, Ralston et al.4 (page 526) describe a form of trogocytosis carried out by the parasite Entamoeba histolytica, and suggest that this process mediates the destruction of intestinal cells that is seen in amoebiasis — the gastrointestinal infection caused by these unicellular organisms.

Trogocytosis in immune cells requires the transduction of signals from the acceptor-cell surface by means of kinase enzymes such as Src, Syk and PI3K, and by modulation of the cell's cytoskeleton (which is rich in the protein actin) and of intracellular calcium-ion (Ca2+) levels2,5. It is a rapid process, occurring within minutes of co-culturing the participant cells in vitro2. Notably, despite the exchange of material, neither the antigen-presenting cell nor the lymphocyte dies following trogocytosis.

In the first description of the process3, it was proposed that trogocytosis may have evolved as a way for cells to acquire nourishment from other cells, and later as a means of intercellular communication. The hypothesis of an ancient origin for trogocytosis is now supported by Ralston and colleagues' observation of a similar mechanism in E. histolytica, an ancient organism. However, unexpectedly, this form of trogocytosis enhances the parasite's virulence, and results in killing of the target cells.

During amoebiasis, E. histolytica resides in the colon of an infected individual, where it depletes it of mucus, interacts with the exposed enterocyte cells lining the colon, dismantles the junctions between them and causes their death by lysis. The previous model6 for the parasite's action was that it attaches itself to host cells and kills them, by an as-yet unclear mechanism involving the insertion of 'amoebapore' peptides into the cell membrane and subsequent lysis. It was also thought that the parasites engulf and ingest dying enterocytes by phagocytosis. But Ralston et al. instead show that the parasite ingests pieces of the host cell, and that this nibbling occurs in a repeated manner that ends up killing the cell. Once killing is achieved, the amoebae move on (Fig. 1).

Figure 1: Amoebic trogocytosis.
Figure 1

Ralston et al.4 have described trogocytosis by Entamoeba histolytica, in which the parasites tear off and ingest patches of host cells, resulting in their death. The interaction between the cells is mediated by abundant surface molecules, including glycoproteins and their attached carbohydrate chains. The cell-to-cell contact is then stabilized through adhesion molecules (not shown), and cytoskeletal activity in the parasite is probably involved in generating the force required to pinch off the host-cell membrane. This transfer of cellular material causes changes in intracellular calcium-ion levels and triggers signalling pathways in both cells. The activity of Src, Syk and PI3K enzymes contributes to this process and leads to 'priming' of the parasites, which amplifies subsequent ingestion. After successive nibbling events, the host cell dies and the parasite moves on.

This trogocytosis-like process is fundamentally different from amoebic phagocytosis, in which the parasite entirely ingests cells such as red blood cells (including dead cells). Although it is not known what determines the parasite's choice between phagocytosis and trogocytosis, some of the authors' findings point to mechanisms similar to those suggested in immune cells7 that can perform trogocytosis in parallel with phagocytosis. For instance, both processes require an active actin-rich cytoskeleton and associated signalling pathways.

Interestingly, the authors' data show that parasites that have previously performed trogocytosis are 'primed' for higher ingestion activity and elicit more host-cell killing than parasites that have not, demonstrating that trogocytosis changes the parasites' behaviour. The authors have also produced images of trogocytosis in living tissue for the first time, and show that the process is required for the parasites to invade the tissue, leading to the pathogenic consequences for the host. They further show that the parasites can trogocytose all of the cell types tested, including enterocytes, lymphocytes, intestinal-tissue cells and red blood cells; because these cells have different surface constituents, it seems likely that a ubiquitous interaction occurs at the cell surfaces during trogocytosis.

It can thus be argued that the first step in amoebic trogocytosis — cell-to-cell attachment — is mediated by general components of the cell surface (for example, the glycocalyx, which is rich in glycoproteins and glycolipids), rather than by specific cell receptors such as the T-cell receptor (TCR), as is observed in immune-cell trogocytosis. The most relevant glycosylated (carbohydrate-containing) components on the parasite cell surface, in terms of abundance, are lipopeptidophosphoglycans and Gal/GalNAc lectin6. Glycosylated residues on these amoebic components might become attached to glycosylated components on the donor cells. The data obtained by Ralston et al. support this hypothesis, because Gal/GalNAc lectin is essential for the process.

Despite their respective cell specificity and ubiquity, there are interesting correlations between the TCR and Gal/GalNAc lectin in terms of signal-transduction characteristics: antigens bind to the TCR with relatively low affinity, similar to the predicted weak interactions between glycosylated residues and the Gal/GalNAc lectin; the activation of both intracellular signalling pathways involves the dynamic linking of the cell-surface molecules into microclusters8,9 and requires a short cytoplasmic domain; and both pathways are associated with Src-kinase activity in the acceptor cell. However, these are only correlated features, because there is no evidence for structural homology between the TCR and Gal/GalNAc lectin.

It is also interesting to speculate on the significance of the intensification of amoebic trogocytosis in primed parasites. One possible explanation is that surface components of the host cell activate specific signalling pathways that enhance the parasite's affinity for extracellular carbohydrates. This idea is based on recent findings indicating that carbohydrate metabolism is involved in amoebic pathogenesis10. Are these signals necessary for killing donor cells by amoebic trogocytosis, but not for lymphocytic trogocytosis? Comprehensive comparisons of gene expression between primed and naive parasites (and in lymphocytes) might help to explain the roles of these activated signals. Further studies may also reveal whether amoebic trogocytosis and phagocytosis occur simultaneously, and what specific signals result from each process. But although such details remain to be determined, this new concept of amoebic trogocytosis is important for understanding not only amoebiasis, but also host–pathogen interactions in other systems and in immune-cell function and interactions.


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  1. Nancy Guillén is in the Department of Cell Biology and Infection, Institut Pasteur, Paris 75015, France.

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Correspondence to Nancy Guillén.

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