Ivermectin inhibits extracellular vesicle secretion from parasitic nematodes

Abstract

Lymphatic filariasis (LF) is a disease caused by parasitic filarial nematodes that is endemic in 49 countries and affects or threatens over 890 million people. Strategies to control LF rely heavily on mass administration of anthelmintic drugs including ivermectin (IVM), a macrocyclic lactone drug considered an Essential Medicine by the WHO. However, despite its widespread use the therapeutic mode of action of IVM against filarial nematodes is not clear. We have previously reported that filarial nematodes secrete extracellular vesicles (EVs) and that their cargo has immunomodulatory properties. Here we investigate the effects of IVM and other anti-filarial drugs on parasitic nematode EV secretion, motility, and protein secretion. We show that inhibition of EV secretion was a specific property of IVM, which had consistent and significant inhibitory effects across nematode life stages and species (with the exception of male parasites). IVM inhibited EV secretion, but not parasite motility, at therapeutically relevant concentrations. Protein secretion was inhibited by IVM in the microfilariae stage, but not in any other stage tested. Our data provides evidence that inhibiting the secretion of immunomodulatory EVs by parasitic nematodes could explain, at least in part, IVM mode of action and provides a phenotype for novel drug discovery.

Sensory cilia act as a specialized venue for regulated extracellular vesicle biogenesis and signaling

“…Environmentally released EVs are instrumental effectors used by parasitic worms to manipulate the host immune system to initiate and maintain infections. 48 The anthelmintic drug ivermectin inhibits EV secretion 49 and is considered an essential drug by the World Health Organization, yet its therapeutic mechanism of action is not clear. One current hypothesis is that ivermectin regulates the release of excretory-secretory products from parasites.…”

Extracellular vesicles as novel assay tools to study cellular interactions of anti-infective compounds – A perspective

“…In this section, we present several EV-based assays, which hold potential for further advancement and adaptation for various types of vesicles. In future, such assays can become more and more applicable in the curse of further progress in EV isolation [113][114][115][116][117][118].…”

Spatial transcriptomics reveals antiparasitic targets associated with essential behaviors in the human parasiteBrugia malayi

“…[37][38][39][40][41] In microfilariae, the ES apparatus is a hallmark and essential structure consisting of a pore and vesicle leading to a single excretory cell via a cytoplasmic bridge. 42 Ivermectin is thought to disrupt microfilarial ES protein and exosome release through binding to ion channels in the vicinity of the ES vesicle 14,16,17 ; however, these structures become inconspicuous through development. 37,38,40,43,44 To help pinpoint the ES in adult female B. malayi, the relative organization of head structures across Clade III 45,46 nematodes was collected from available literature (Figure 2A).…”

“…Current anthelmintics target or dysregulate parasite cell integrity, neuromuscular control, reproductive potential, and the secretion of parasite molecules necessary for the establishment and maintenance of parasitism. [13][14][15][16][17][18] The development of macrofilaricidal (adult-killing) drugs can be hastened by an improved knowledge of tissues that underpin survival in adult parasites.…”