Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi

Abstract

Ivermectin (IVM) is a broad-spectrum anthelmintic used in filariasis control programs. By binding to nematode glutamate-gated chloride channels (GluCls), IVM disrupts neurotransmission processes regulated by GluCl activity. IVM treatment of filarial infections is characterized by an initial dramatic drop in the levels of circulating microfilariae, followed by long-term suppression of their production, but the drug has little direct effect on microfilariae in culture at pharmacologically relevant concentrations. We localized Brugia malayi GluCl expression solely in a muscle structure that surrounds the microfilarial excretory-secretory (ES) vesicle, which suggests that protein release from the ES vesicle is regulated by GluCl activity. Consistent with this hypothesis, exposure to IVM in vitro decreased the amount of protein released from microfilariae. To better understand the scope of IVM effects on protein release by the parasite, three different expression patterns were identified from immunolocalization assays on a representative group of five microfilarial ES products. Patterns of expression suggest that the ES apparatus is the main source of regulated ES product release from microfilariae, as it is the only compartment that appears to be under neuromuscular control. Our results show that IVM treatment of microfilariae results in a marked reduction of protein release from the ES apparatus. Under in vivo conditions, the rapid microfilarial clearance induced by IVM treatment is proposed to result from suppression of the ability of the parasite to secrete proteins that enable evasion of the host immune system. filarial nematode | macrocyclic lactone | glutamate-gated chloride channels

Characterization of the target of ivermectin, the glutamate-gated chloride channel, fromAnopheles gambiae

“…The primary target of IVM is the invertebrate glutamate-gated chloride channel (GluCl) (Cully et al, 1994(Cully et al, , 1996Janssen et al, 2007Janssen et al, , 2010McCavera et al, 2009;Moreno et al, 2010), though it also has efficacy against other members of the invertebrate Cys-loop family of neurotransmitter receptors including the γ-aminobutyric acid- (Brown et al, 2012), histamine- (Zheng et al, 2002) and pHsensitive chloride channels (Schnizler et al, 2005). Because IVM is used to control and treat parasitic nematode diseases (Õmura, 2008), the majority of research on IVM targets has occurred in nematodes or model organisms, but the function of GluCl in mosquito disease vectors is unknown.…”

Subunit stoichiometry and arrangement in a heteromeric glutamate-gated chloride channel

“…Because the GluClR is chloride-selective, IVM causes sustained hyperpolarization across postsynaptic membranes in the parasitic nematodes. This long-term hyperpolarization leads to suppression of excitation in motor neurons and inhibition of locomotion (19); inhibition of the pharyngeal muscle activity, which interrupts with feeding behavior (20); and interruption of secretion processes that are crucial for evading the host immune system (21).…”

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

“…"Mazzoti reactions") are a necessary component in the death of filariae or merely a response to dead and damaged worms [16] and the concomitant liberation of somatic antigens and Wolbachia endobacteria [32,33], the former has been proposed due to a general lack of efficacy of SAFD at physiological levels in vitro against filariae [34,35]. Further, various 'immuno-pharmacological' modes of action have been proposed for SAFD, including the prevention of immuno-modulatory secretions from mf by IVM [36] and the induction of host inducible nitric oxide and cyclooxygenase pathways by DEC [24]. Thus, it was important to validate anti-filarial responses in the SCID model against an immunologically intact WT control, where possible.…”