Open AccessIntestinal UDP-glucuronosyltransferase as a potential target for the treatment and prevention of lymphatic filariasis
Author(s) -
Alexander Flynn,
Michael Joyce,
Roger R. Taylor,
Sasisekhar Bennuru,
Alyssa R Lindrose,
Spencer L. Sterling,
C. Paul Morris,
Thomas B. Nutman,
Edward Mitre
Publication year - 2019
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0007687
Subject(s) - brugia malayi , lymphatic filariasis , microfilaria , diethylcarbamazine , immunology , pharmacology , indoleamine 2,3 dioxygenase , loa loa , brugia pahangi , wuchereria bancrofti , filariasis , albendazole , biology , helminths , biochemistry , ecology , tryptophan , amino acid
Lymphatic filariasis (LF), a morbid disease caused by the tissue-invasive nematodes Wuchereria bancrofti , Brugia malayi , and Brugia 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 evaluate B . 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 of Bm-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, sulfinpyrazone and probenecid, for in vitro activity against B . malayi . There were marked macrofilaricidal effects at concentrations achievable in humans and very little effect on microfilariae. In addition, we observed that probenecid and sulfinpyrazone exhibit a synergistic macrofilaricidal effect when used in combination with albendazole. The results of this study demonstrate that Bm-UGT is an essential protein for adult worm survival. Lack of prior IgE sensitization in infected and endemic populations suggest it may be a feasible vaccine candidate. The finding that sulfinpyrazone and probenecid have in vitro effects against adult B . malayi worms suggests that these medications have promise as potential macrofilaricides in humans.