International Journal for Parasitology: Drugs and Drug Resistance
The use of microﬁlaricidal drugs for the control of onchocerciasis and lymphatic ﬁlariasis (LF) necessitates prolonged yearly dosing. Prospects for elimination or eradication of these diseases would be enhanced by the availability of a macroﬁlaricidal drug. Flubendazole (FLBZ), a benzimidazole anthel- mintic, is an appealing candidate. FLBZ has demonstrated potent macroﬁlaricidal effects in a number of experimental rodent models and in one human trial. Unfortunately, FLBZ was deemed unsatisfactory for use in mass drug administration campaigns due to its limited oral bioavailability. A new formulation that enables sufﬁcient bioavailability following oral administration could render FLBZ an effective treatment for onchocerciasis and LF. Identiﬁcation of drug-derived effects is important in ascertaining a dosage regimen which is predicted to be lethal to the parasite in situ. In previous histological studies, exposure to FLBZ induced damage to tissues required for reproduction and survival at pharmacologically relevant concentrations. However, more precise and quantitative indices of drug effects are needed. This study assessed drug effects using a transcriptomic approach to conﬁrm effects observed histologically and to identify genes which were differentially expressed in treated adult female Brugia malayi. Comparative analysis across different concentrations (1m M and 5mM) and durations (48 and 120 h) provided an overview of the processes which are affected by FLBZ exposure. Genes with dysregulated expression were consistent with the reproductive effect s observed via histology in our previous studies. This study revealed transcriptional changes in genes involved in embryo development. Additionally, signiﬁcan't downregulation was observed in genes encoding cuticle components, which may reﬂect changes in developing embryos, the adult worm cuticle or both. These data support the hypothesis that FLBZ acts predominantly on rapidly dividing cells, and provides a basis for selecting molecular markers of drug-induced damage which may be of use in predicting efﬁcacious FLBZ regimens.
Filariasis, Macroﬁlaricide, Benzimidazole, RNAseq, Reproduction, Cuticle, Flubendazole
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2211-3207/© 2016 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
O'Neill, Maeghan; Ballesteros, Cristina; Tritten, Lucienne; Burkman, Erica; Zaky, Weam I.; Xia, Jianguo; Moorhead, Andrew; Williams, Steven A.; and Geary, Timothy G., "Profiling the Macrofilaricidal Effects of Flubendazole on Adult Female Brugia Malayi Using RNAseq" (2016). Biological Sciences: Faculty Publications, Smith College, Northampton, MA.