Intestinal UDP-glucuronosyltransferase as a potential target for the treatment and prevention of lymphatic filariasis

by Alexander F. Flynn, M. Gordon Joyce, Rebekah T. Taylor, Sasisekhar Bennuru, Alyssa R. Lindrose, Spencer L. Sterling, C. Paul Morris, Thomas B. Nutman, Edward Mitre Lymphatic filariasis (LF), a morbid disease caused by the tissue-invasive nematodesWuchereria bancrofti,Brugia malayi, andBrugia timori, affects millions of people worldwide. Global eradication efforts have significantly reduced worldwide prevalence, but complete elimination has been hampered by limitations of current anti-filarial drugs and the lack of a vaccine. The goal of this study was to evaluateB.malayi intestinal UDP-glucuronosyltransferase (Bm-UGT) as a potential therapeutic target. To evaluate whether Bm-UGT is essential for adult filarial worms, we inhibited its expression using siRNA. This resulted in a 75% knockdown ofBm-ugt mRNA for 6 days and almost complete suppression of detectable Bm-UGT by immunoblot. Reduction in Bm-UGT expression resulted in decreased worm motility for 6 days, 70% reduction in microfilaria release from adult worms, and significant reduction in adult worm metabolism as detected by MTT assays. Because prior allergic-sensitization to a filarial antigen would be a contraindication for its use as a vaccine candidate, we tested plasma from infected and endemic normal populations for Bm-UGT-specific IgE using a luciferase immunoprecipitation assay. All samples (n = 35) tested negative. We then tested two commercially available medicines known to be broad inhibitors of UGTs, sulfin...
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research