All ETDs from UAB

Advisory Committee Chair

Frances Lund

Advisory Committee Members

Amy Weinmann

Andre Ballesteros-Tato

John Kearney

Lesley Smythies

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Schistosomiasis, also known as bilharzia, is the third most common parasitic infection worldwide and a major source of morbidity and mortality in developing countries. Caused by trematodes in the genus Schistosoma, this parasitic disease has no vaccine therapy and resources for drug development are scarce. Despite an unknown mechanism of action, praziquantal has become the primary source of treatment due to its efficacy against all species of Schistosoma. However, with increased drug resistance in endemic areas and low activity against immature parasites, relying on this single drug is unsustainable and risky. Hence, there is a growing need for new, safe and effective therapies against schistosomiasis. Schistosoma mansoniNAD catabolizing enzyme (SmNACE) is a protein conserved across multiple members of the genus Schistosoma. SmNACE hydrolyzes nicotinamide adenine dinucleotide (NAD) into nicotinamide (NAM) which can be transported across the cell membrane and used in the salvage pathway of NAD synthesis. In mammals, the two pathways of NAD production include de novo synthesis from amino acid precursors and the salvage pathway in which nicotinamide-containing precursors are recycled into NAD. Interestingly, we observed only orthologues of NAD salvage-specific genes in schistosomes. This suggests that S. mansoni relies solely on the salvage pathway for the production of NAD which is critical for cell survival and plays an important role in many cellular processes Indeed, incubation of adult parasites with the SmNACE inhibitor CMP1significantly impacted NAD uptake and impaired egg production. Furthermore, direct inhibition of the NAD salvage pathway using FK866 significantly reduced parasite intracellular NAD, intracellular lactic acid, egg production, survival and mobility. Importantly, in vivo blockade of the NAD salvage pathway using FK866decreased egg and worm burden in mice that were infected with S. mansoni. Furthermore, S. mansoni-infected mice had lower degrees of splenomegaly and hepatomegaly, and a reduced number of granulomas in the liver. In conclusion, our data show that pharmacological inhibition of the NAD salvage pathway significantly impairs S. mansoni reproduction and survival both in vitro and in vivo and suggest that targeting the NAD salvage pathway is a promising therapeutic approach for the treatment of schistosomiasis.

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