Unique glycan and lipid composition of helminth-derived extracellular vesicles may reveal novel roles in host-parasite interactions

Highlights

• Helminth extracellular vesicles (EVs) share common proteins with those from mammals.

• Two recent studies have identified divergence in composition.

• Differential lipid and glycan profiles have been identified in helminth EVs.

• Is the composition of helminth EVs indicative of unique biological function?

Abstract

Although the study of helminth-derived extracellular vesicles (EVs) is in its infancy, proteomic studies of EVs from representatives of nematodes, cestodes and trematodes have identified homologs of mammalian EV proteins including components of the endosomal sorting complexes required for transport and heat-shock proteins, suggesting conservation of pathways of EV biogenesis and cargo loading between helminths and their hosts. However, parasitic helminth biology is unique and this is likely reflected in helminth EV composition and biological activity. This opinion article highlights two exceptional studies that identified EVs released by Heligmosomoides polygyrus and Fasciola hepatica which display differential lipid and glycan composition, respectively, when compared with EVs derived from mammalian cells. Furthermore, we discuss the potential implications of helminth EV lipid and glycan composition upon helminth infection and host pathology. Future studies, focusing on the unique composition and functional properties of helminth EVs, may prove crucial to the understanding of host-parasite communication.

Introduction

The study of extracellular vesicles (EVs) is a relatively young field and the study of helminth EVs is newer still, however research is advancing rapidly and the importance of EV biology in health and disease is increasingly apparent. In the race to understand helminth EV biology we frequently look to the parent field for comparisons and it is likely beneficial to do so. Vesicles are released from organisms within the three domains of Bacteria, Archaea and Eukaryota (Woith et al., 2019) and components of endosomal sorting complexes required for transport (ESCRT) I-III, identified as key factors in mammalian EV biogenesis (Colombo et al., 2013), show conservation throughout eukaryotes (Leung et al., 2008). Indeed, ESCRT components have been identified in proteomic analyses of EVs from nematodes (Buck et al., 2014), cestodes (Nicolao et al., 2019) and trematodes (Cwiklinski et al., 2015). Furthermore, heat-shock proteins (HSPs), which function as chaperones, are commonly detected in mammalian (Niel et al., 2018) and multiple helminth EV proteomes (Eichenberger et al., 2018) including those from Ascaris suum (Hansen et al., 2019) and Fasciola hepatica (Cwiklinski et al., 2015). Therefore, it is likely that pathways of EV biogenesis and cargo loading show conservation between helminths and mammals.

However, the evolutionary diversity within helminths and their complex life cycles that can include intermediate hosts and biologically harsh niches, for example in the gastrointestinal tract with high proteolytic enzyme activity and peristaltic action, to which parasite biology has uniquely adapted and this may be reflected in helminth EV composition and function. EVs from several helminths have been characterised to date, with protein and micro RNA (miRNA) cargo analysed, and functional studies have identified examples of parasite EV-mediated immune modulation (Coakley et al., 2015, Zakeri et al., 2018, Mardahl et al., 2019).

This current opinion piece highlights two examples where helminth EV lipid and glycan composition diverge significantly from that commonly held for mammalian EVs, and will discuss how this may impact helminth EV biology and the implications for host-parasite interactions. Although the number of lipid and glycan studies of mammalian EVs are limited, it is becoming clear that these components are highly bioactive, contributing to cell uptake of EVs and mediating immune modulation in diseases such as cancer (Gerlach and Griffin, 2016, Record et al., 2018).

Helminth-derived lipids mediate immune modulation in host cells as demonstrated by lysophosphatidylserine and lysophosphatidylcholine, from the blood-residing trematode Schistosoma mansoni, activation of host-cell toll-like receptor (TLR)2. Lysophosphatidylserine induced Th2 polarisation of dendritic cells (van der Kleij et al., 2002) whilst lysophosphatidylcholine induced M2 polarisation of peritoneal macrophages (Assunção et al., 2017) and the secretion of transforming growth factor (TGF)β from eosinophils (Magalhães et al., 2019). It has been postulated that EVs may provide a mechanism for the delivery of such lipids to host cells by S. mansoni (Coakley et al., 2019). The TLR4 dependent immunomodulatory effects of the glycoprotein ES-62, secreted by the filarial nematode of rodents Acanthocheilonema viteae (Harnett and Harnett, 1993), is mediated by the phosphorylcholine moieties with recombinant ES-62 being ineffective, suggesting post-translational modification of helminth proteins is crucial to their immune modulatory function (Goodridge et al., 2007). As such, helminth-derived glycans are contributors to the induction of a Th2-dominated response in the host and drivers in alternative activation of antigen presenting cells (Harn et al., 2009, Kuijk and van Die, 2010, Tundup et al., 2012). Indeed, the Th2-inducing effects of S. mansoni soluble egg antigens and soluble products from the filarial nematode Brugia malayi were attenuated by sodium metaperiodate treatment (Okano et al., 1999, Tawill et al., 2004), indicating a requirement for helminth glycans in the observed immunomodulatory effects. Identifying where helminth EV biology deviates from that of mammalian EVs, and investigating the biological consequences of their distinct compostion such as lipid and glycan profiles in the studies discussed here, will further our understanding of host-parasite communication and could enable the identification of truly novel translational applications for helminth EVs or their constituents.