Abstract
BackgroundThe trehalose metabolic enzymes have been considered as potential targets for drug or vaccine in several organisms such as Mycobacterium, plant nematodes, insects and fungi due to crucial role of sugar trehalose in embryogenesis, glucose uptake and protection from stress. Trehalose-6-phosphate phosphatase (TPP) is one of the enzymes of trehalose biosynthesis that has not been reported in mammals. Silencing of tpp gene in Caenorhabditis elegans revealed an indispensable functional role of TPP in nematodes.Methodology and Principal FindingsIn the present study, functional role of B. malayi tpp gene was investigated by siRNA mediated silencing which further validated this enzyme to be a putative antifilarial drug target. The silencing of tpp gene in adult female B. malayi brought about severe phenotypic deformities in the intrauterine stages such as distortion and embryonic development arrest. The motility of the parasites was significantly reduced and the microfilarial production as well as their in vitro release from the female worms was also drastically abridged. A majority of the microfilariae released in to the culture medium were found dead. B. malayi infective larvae which underwent tpp gene silencing showed 84.9% reduced adult worm establishment after inoculation into the peritoneal cavity of naïve jirds.Conclusions/SignificanceThe present findings suggest that B. malayi TPP plays an important role in the female worm embryogenesis, infectivity of the larvae and parasite viability. TPP enzyme of B. malayi therefore has the potential to be exploited as an antifilarial drug target.
Highlights
Lymphatic filariasis (LF), caused by mosquito transmitted filarial parasites, Wuchereria bancrofti, Brugia malayi and B. timori has been identified as a second leading cause of permanent and long term disability
We demonstrate for the first time the biological function of tpp in filarial parasite, B. malayi by in vitro RNAi mediated gene silencing and validated it as a putative antifilarial drug target
Trehalose-6-phosphate phosphatase (TPP) enzyme is involved in the biosynthesis of the trehalose where it dephosphorylates trehalsoe-6-phosphate to yield trehalose
Summary
Lymphatic filariasis (LF), caused by mosquito transmitted filarial parasites, Wuchereria bancrofti, Brugia malayi and B. timori has been identified as a second leading cause of permanent and long term disability. LF control relies on community-wide mass distribution of diethylcarbamazine or ivermectin in combination with albendazole [1] These drugs are principally microfilaricidal and not much effective on the adult worms, repeated treatment is required over many years for interrupting the transmission. The synthesis of trehalose in the nematodes proceeds in the classical pathway and is catalysed by the action of two enzymes: i) TPS, which catalyses the transfer of glucose from uridine diphosphate (UDP)-glucose to glucose-6-phosphate to produce trehalose-6-phosphate (T6P); and ii) TPP, which converts T6P to free trehalose and Pi [11] Both the enzymes represent a set of attractive drug targets as no homologues are present in the Author Summary. Silencing of tpp gene in Caenorhabditis elegans revealed an indispensable functional role of TPP in nematodes
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