Extracellular vesicles: new targets for vaccines against helminth parasites

Abstract

The hunt for effective vaccines against the major helminth diseases of humans has yet to bear fruit despite much effort over several decades. No individual parasite antigen has proved to elicit full protective immunity, suggesting that combinatorial strategies may be required. Recently it has been discovered that extracellular vesicles released by parasitic helminths contain multiple potential immune modulators, which could together be targeted by a future vaccine. Increasing knowledge of helminth extracellular vesicle components, both enclosed by and exposed on the membrane, will open up a new field of targets for an effective vaccine. This review discusses the interactions between helminth extracellular vesicles and the immune system discovered thus far, and the advantages of targeting these lipid-bound packages with a vaccine. In addition, we also comment upon specific antigens that may be the best targets for an anti-helminth vaccine. In the future, extensive knowledge of the parasites' full arsenal in controlling their host may finally provide us with the ideal target for a fully effective vaccine.

Keywords: Exosomes; Extracellular vesicle; Helminth; Parasite antigen; Vaccine.

Graphical abstract

Fig. 1

Overview of specific vesicle biogenesis and secretion pathways. Intra-luminal vesicles (ILVs) are formed within early endosomes via inward budding, retaining membrane proteins, lipids and other cytosolic contents of the parent cell (1). Endosomes mature to become late endosomes/multivesicular bodies (MVBs) (2) and degrade their contents via fusion with the lysosome (3) or release their ILVs into the extracellular environment (where they are now classed as “exosomes”) following fusion with the plasma membrane (4). Other methods of secretion include ‘budding’ of larger vesicles, such as microparticles, microvesicles and ectosomes, directly from the plasma membrane (5) or following programmed cellular death, whereby vesicles known as apoptotic bodies “bleb” from the cellular surface (6). Images are adapted from Servier Medical Art by Servier (http://smart.servier.com/) and modified by the authors under the following terms: Creative Commons Attribution 3.0 Unported (CC BY 3.0).

Fig. 2

Vesicle release from helminth parasites. Both platyhelminths and nematodes have been found to release extracellular vesicles (EVs) from the gastrodermis (1). In nematodes, EVs released in the intestines may be released into the host via the anterior (2) or posterior (3) openings. EVs of Brugia malayi have also been found to be secreted from the excretory/secretory pore (4). In the case of platyhelminths, EVs can be shed directly from the tegument itself into the surrounding environment (5). Images are adapted from Servier Medical Art by Servier (http://smart.servier.com/) and modified by the authors under the following terms: Creative Commons Attribution 3.0 Unported (CC BY 3.0).

Fig. 3

Proposed methods of exosome uptake. Exosomes can generate numerous responses in recipient cells, and are suggested to do so through at least three different mechanisms. Exosomes and other vesicles might directly fuse to the plasma membrane of the recipient cell, although the biological pathways involved in this are still poorly understood (1). Exosomes might also directly target receptors on the exterior surface of the recipient cell, driving host responses e.g. by co-stimulation through receptor-ligand interactions (2). Exosomes are also known to be taken up by recipient cells by phagocytosis, macro/micropinocytosis or endocytosis (caveolin/clathrin-dependent, receptor or antibody-mediated) (3). From our studies, we showed that antibodies enhance uptake of extracellular vesicles (EVs) into recipient cells, which are subsequently targeted for lysosomal degradation (4). Alternatively, internalised exosomes and other vesicles might utilise endosomal escape to release their contents directly or indirectly into the recipient cell cytosol (5). Images are adapted from Servier Medical Art by Servier (http://smart.servier.com/) and modified by the authors under the following terms: Creative Commons Attribution 3.0 Unported (CC BY 3.0).