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 of the world 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.

Helminth extracellular vesicles: Interactions with the host immune system

“…Ivermectin is suggested to work via activation of glutamate-gated chloride channels, leading to hyperpolarisation of cell membranes and so paralysis, however ivermectin can also affect other pathways and its mechanism of action is not fully understood ( Laing et al, 2017 ). Effects on EV secretion by ivermectin are seen at far lower concentrations than that needed for motility effects, and closer to the concentrations found after treatment in vivo ( Loghry et al, 2020 ). This suggests that a therapeutic mode of action of ivermectin could involve inhibition of helminth EV secretion, preventing immunomodulation of the host.…”

“…Ivermectin, a drug already used widely to treat helminth infections in both humans and animals, has been found to inhibit EV release in B. malayi, D. immitis and A. suum ( Harischandra et al, 2018 ; Loghry et al, 2020 ). Other anti-helminth drugs, including albendazole and levamisole, do not show inhibition of EV secretion, and no effect of ivermectin was seen on a D. immitis strain that has resistance to the drug, suggesting a specific mode of action for ivermectin ( Loghry et al, 2020 ; Harischandra et al, 2018 ).…”

“…Ivermectin, a drug already used widely to treat helminth infections in both humans and animals, has been found to inhibit EV release in B. malayi, D. immitis and A. suum ( Harischandra et al, 2018 ; Loghry et al, 2020 ). Other anti-helminth drugs, including albendazole and levamisole, do not show inhibition of EV secretion, and no effect of ivermectin was seen on a D. immitis strain that has resistance to the drug, suggesting a specific mode of action for ivermectin ( Loghry et al, 2020 ; Harischandra et al, 2018 ). Ivermectin is suggested to work via activation of glutamate-gated chloride channels, leading to hyperpolarisation of cell membranes and so paralysis, however ivermectin can also affect other pathways and its mechanism of action is not fully understood ( Laing et al, 2017 ).…”

Expression and secretion of circular RNAs in the parasitic nematode,Ascaris suum

“…When worms were treated with 0.1 µM (Figure 5B) or 1 µM (Supplemental Figure 4) IVM we did not observe any decrease in AgR007_g109_t01: 1908852-1911650 or AgB08X_g209_t01:3249044-3252560 abundance in isolated EVs (Figure 5B, N=3). This observation was perhaps surprising, given the strong and consistent evidence for an inhibitory effect of IVM on EV secretion in parasitic nematodes, including Ascaris (Loghry et al, 2020; Harischandra et al, 2018). This may point to other non-EV mediated routes of circRNA release from these worms.…”

The Secretome of Filarial Nematodes and Its Role in Host-Parasite Interactions and Pathogenicity in Onchocerciasis-Associated Epilepsy

“…By playing an important role in both infection and pathology, the secretome of filarial parasites is therefore a promising target for further investigation. Moreover, it has been shown that the anti-filarial drug ivermectin inhibits the excretory-secretory ability of microfilariae, resulting in their death ( Moreno et al., 2010 ; Carithers, 2017 ; Harischandra et al., 2018 ; Loghry et al., 2020 ).…”