Abstract
Glutamate-gated chloride channels (GluCl) are targets for avermectin/milbemycin (A/M) anthelmintics such as ivermectin that cause paralysis of somatic and pharyngeal muscles in gastrointestinal nematodes. Ivermectin is useful for onchocerciasis control programs because of its activity against microfilariae that often cause ocular disease and severe dermatitis. However, mechanisms responsible for reduced microfilaria production by adult worms following ivermectin treatment are poorly understood. We synthesized subunit-specific RNA probes for the Brugia malayi GluCl gene avr-14 (BmAVR-14) to localize expression of this gene in adult filarial worms. Both subunits of BmAVR-14 exhibited very similar expression patterns. In female worms, strong expression signals were detected in the ovary, developing embryos and lateral hypodermal chords, with moderate expression in the uterus wall adjacent to stretched microfilariae. These genes were also highly expressed in adult male worms (in spermatogonia, in the wall of the vas deferens, and in the lateral chords, but not in mature spermatozoa). In addition, avr-14 was highly expressed in somatic muscles adjacent to the terminal end of the vas deferens which contains mature sperm. These results show that avr-14 is highly expressed in B. malayi developing embryos and reproductive tissues, and they provide evidence for the involvement of GluCl in gamete production and embryogenesis in filarial worms. This may explain the observed suppression of microfilaria (Mf) production by female worms following treatment with avermectin/milbemycin anthelmintics.
Highlights
Parasitic nematodes cause major diseases in humans, livestock, and crops (Broughan and Wall, 2007; Coles, 2001; Chitwood, 2003; Hotez et al, 2007)
Prior studies have used reporter gene constructs that could not distinguish between the two splice variants in C. elegans and subunitspecific antibodies in Haemonchus contortus (Dent et al, 2000; Jagannathan et al, 1999; Portillo et al, 2003)
A recent study used an anti-peptide antibody to show that BmAVR-14 was expressed in a muscle structure that surrounds the Mf excretory–secretory (ES) vesicle (Moreno et al, 2010)
Summary
Parasitic nematodes cause major diseases in humans, livestock, and crops (Broughan and Wall, 2007; Coles, 2001; Chitwood, 2003; Hotez et al, 2007). Nematodes are responsible for several important neglected tropical diseases of humans including lymphatic filariasis, onchocerciasis, and soil transmitted helminthiasis (STH) which affect a large portion of the world’s population (Hotez et al, 2007). GluCl are members of the Cys-loop ligand-gated ion channel family. While they are only present in invertebrates (Cleland, 1996), they are distantly related to vertebrate c-aminobutyric acid-A (GABAA) receptors (Vassilatis et al, 1997b). Six GluCl genes have been identified in C. elegans that encode as many as eight protein subunits that are formed by alternative splicing
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