Inhibition of release of intestinal extracellular vesicles in Ascaris suum and immune modulation by the anthelmintic ivermectin
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Ivermectin is an important broad-spectrum anthelmintic used to treat nematode parasites including gastro-intestinal infections of humans and animals. The mode of action for Ivermectin is understood to involve activation of inhibitory glutamate-gated chloride channels (GluCls). Ivermectin has also been reported to inhibit the release of extracellular vesicles (EVs). We found that EVs are released from the whole intestine of the gastro-intestinal parasite, Ascaris suum . Proteomic analysis identified 1,574 proteins within these intestinal EVs, including 96 nematode proteins with putative immune-associated functions based on homology to proteins involved in host immune processes and 130 proteins with predicted digestive functions. Comparative analysis following ivermectin exposure revealed 38 differentially abundant proteins that included the putative immune-related proteins: transthyretin-like proteins, a small heat-shock antigen, a phospholipase A2, and the NF-κB subunit p105. Thus, ivermectin modulated the potential immune-related cargo of intestinal EVs. The ivermectin inhibition of intestinal EV release was concentration-dependent with an IC50 of 64 nM. We also identified the expression of GluCl subunit receptor genes in the Ascaris intestine. The potent inhibitory effect of ivermectin on the release of these EVs from the nematode intestine and the expression of GluCl channel subunits sheds further light on the site and mechanisms of action of this important anthelmintic.
Graphical Abstract
Extracellular vesicles have become recognized as important mediators of intercellular communication and host–pathogen interactions, but the tissue origins and control of helminth-derived EVs and the mechanisms regulating their release remain poorly understood and may include the E/S pore and anal pore. Ivermectin is an important drug for treating nematode parasite infections. Significantly, we find that release of intestinal EVs ( Int.) that carry immune modulating protein cargo from the nematode parasite intestine to the host is inhibited by the anthelmintic ivermectin with glutamate gated chloride channels.
