Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis.

Tsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce populations of insect pollinator species. Here we present a promising, environment-friendly alternative to current insecticides that targets the insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded and eliminated. RNA interference (RNAi) of either the first two enzymes in the tyrosine degradation pathway (tyrosine aminotransferase (TAT) and 4-hydroxyphenylpyruvate dioxygenase (HPPD)) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, oral administration of NTBC to bumblebees did not affect their survival. Using a novel mathematical model, we show that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current disease elimination programmes.

Tryptophan metabolism in tsetse flies and the consequences of its derangement.

Literature comparing salmon and wild type Glossina morsitans morsitans and that comparing tan and wild type Glossina palpalis palpalis is reviewed. New information is presented on behaviour and biochemistry of salmon and wild type G. m. morsitans. The eye color mutants result from two lesions in the tryptophan to xanthommatin pathway: lack of tryptophan oxygenase in G. m morsitans and failure to produce or retain xanthommatin in eyes (but not in testes) of G. p. palpalis. The salmon allele in G. m. morsitans is pleiotropic and profoundly affects many aspects of fly biology including longevity, reproductive capacity, vision, vectorial capacity and duration of flight, but not circadian rhythms. The tan allele in G. p. palpalis has little effect upon the biology of flies under laboratory conditions, except that tan flies appear less active than normal. Adult tsetse flies metabolize tryptophan to kynurenine which is excreted; fluctuations in activities of the enzymes producing kynurenine suggest this pathway is under metabolic control.