Abstract
Lymphatic filariasis (LF) threatens nearly 20% of the world’s population and has handicapped one-third of the 120 million people currently infected. Current control and elimination programs for LF rely on mass drug administration of albendazole plus diethylcarbamazine (DEC) or ivermectin. Only the mechanism of action of albendazole is well understood. To gain a better insight into antifilarial drug action in vivo, we treated gerbils harbouring patent Brugia malayi infections with 6 mg kg−1 DEC, 0.15 mg kg−1 ivermectin or 1 mg kg−1 albendazole. Treatments had no effect on the numbers of worms present in the peritoneal cavity of treated animals, so effects on gene expression were a direct result of the drug and not complicated by dying parasites. Adults and microfilariae were collected 1 and 7 days post-treatment and RNA isolated for transcriptomic analysis. The experiment was repeated three times. Ivermectin treatment produced the most differentially expressed genes (DEGs), 113. DEC treatment yielded 61 DEGs. Albendazole treatment resulted in little change in gene expression, with only 6 genes affected. In total, nearly 200 DEGs were identified with little overlap between treatment groups, suggesting that these drugs may interfere in different ways with processes important for parasite survival, development, and reproduction.
Highlights
Human infections with filarial nematodes affect about 160 million people worldwide, with many more at risk of infection (Fenwick, 2012)
Drug treatment of the B. malayi infection in gerbils had no effect on the parasite numbers in the peritoneal cavity either 1 day or 7 days after treatment (Table 1)
Treatment of sub-cutaneous B. pahangi infections of gerbils with an oral dose of 0.2 mg kg−1 ivermectin had no effect on adult worm numbers, did not clear circulating Mf, and only reduced their numbers by ∼85% 3 weeks after treatment (Rao et al, 1990; Bosshardt et al, 1995)
Summary
Human infections with filarial nematodes affect about 160 million people worldwide, with many more at risk of infection (Fenwick, 2012). Ivermectin irreversibly activates nematode glutamate-gated chloride channels (Cully et al, 1994; Wolstenholme and Rogers, 2005), including those from filaria (Yates and Wolstenholme, 2004). The expression of these channels in the excretory/secretory pore of Brugia malayi Mf (Moreno et al, 2010) and reproductive tissue of adult females (Li et al, 2014) correlates with the observed inhibition of secretion from Mf (Moreno et al, 2010; Harischandra et al, 2018) and the long-term sterilization of the females caused by the drug (Stolk et al, 2005). DEC has been reported to inhibit arachidonic acid metabolism in Mf (Maizels and Denham, 1992), blocking both cyclooxygenase and lipoxygenase
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