Inhibition of the NAD salvage pathway in schistosomes impairs metabolism, reproduction, and parasite survival

Abstract

NAD, a key co-enzyme required for cell metabolism, is synthesized via two pathways in most organisms. Since schistosomes apparently lack enzymes required for de novo NAD biosynthesis, we evaluated whether these parasites, which infect >200 million people worldwide, maintain NAD homeostasis via the NAD salvage biosynthetic pathway. We found that intracellular NAD levels decline in schistosomes treated with drugs that block production of nicotinamide or nicotinamide mononucleotide–known NAD precursors in the non-deamidating salvage pathway. Moreover, in vitro inhibition of the NAD salvage pathway in schistosomes impaired egg production, disrupted the outer membranes of both immature and mature parasites and caused loss of mobility and death. Inhibiting the NAD salvage pathway in schistosome-infected mice significantly decreased NAD levels in adult parasites, which correlated with reduced egg production, fewer liver granulomas and parasite death. Thus, schistosomes, unlike their mammalian hosts, appear limited to one metabolic pathway to maintain NAD-dependent metabolic processes.

Author summary

Schistosomiasis (snail fever) is a deadly parasitic disease that affects more than 200 million people worldwide and, if not treated, can lead to death. This disease is caused by parasitic worms called schistosomes that feed on the host blood and lay hundreds of eggs each day that damage the liver and kidneys. Therapies to treat schistosomiasis are limited. The most widely-used anti-schistosomal drug, praziquantel, is not effective against immature parasites and adult worms can, in some cases, become resistant to this drug. It is therefore important to find new therapies to treat this deadly disease. In this study, we observed that schistosomes cannot use amino acids to make Nicotinamide Adenine Dinucleotide (NAD)–a key cellular metabolite found in all living organisms. Instead, these parasites salvage NAD by scavenging vitamins from the host. We observed that disruption of this NAD salvage pathway negatively impacts metabolism, reproduction and survival of both adult and immature worms. As such, targeting the parasite’s NAD salvage pathway is a promising therapeutic approach for the treatment of snail fever.