Nuclear option prevents hyperinfection in the Strongyloides worm war.

Humans are fighting a grinding war against parasitic nematodes. More than 100 species of nematode parasites are known to infect humans. Additionally, 1.5 billion people are infected by soil-transmitted helminths worldwide that cause an annual disease burden of 5 million years lost due to disability (YLD) (1). This disease burden is greater than the annual disease burdens of malaria (4 million YLD) and HIV/ AIDS (4.5 million YLD). The soil-transmitted parasite infections crush human health, productivity, and educational development (2). Currently, there are no fully effective vaccines against nematode parasites, and in the absence of adequate sanitation, drug treatment is the main method of control. Despite the numerous soil-transmitted parasitic infections, there are only a few drugs to treat them. Treatment is based on three main classes of drug (anthelmintic): the benzimidazoles (albendazole and mebendazole), the macrocyclic lactones (ivermectin), and the nicotinic compounds (pyrantel). There are concerns about the regular use of these three classes of compounds for mass dose administration because of the potential for development of drug resistance (3). There is a real and urgent need for novel therapeutic approaches to be developed to control these parasites. An innovative model and original therapeutic approach is described in PNAS by Patton et al. (4), who show that the nematode parasite, Strongyloides stercoralis (5), which causes a deadly hyperinfection in immunocompromised humans, can be accurately modeled in NOD.Cg-PrkdcIl2rg/SzJ (NSG) mice, and wonderfully, can be controlled by a DAF-12 nuclear receptor agonist, Δ7-dafachronic acid. This approach provides a novel strategy for treating these lethal hyperinfections and perhaps other parasitic nematodes. Strongyloides stercoralis is a soil-transmitted nematode, currently infecting some 30–100 million people in countries like Vietnam, Central America, and Africa in rural areas where there is limited sanitation. Nematode parasites infect their host by means of a tough third larval stage (L3) that develops after two molts from egg hatching. Once the L3 have gained entry to their host, another molt is triggered, and the parasite adapts to the new host environment and continues to grow to become an adult. There are similarities between the infectious L3 stages of parasitic nematodes and the resistant dauer stage of the model nematode, Caenorhabditis elegans: they are thought to be equivalent. In C. elegans the nuclear receptor, DAF-12, is triggered by dafachronic acids (6), a process that inhibits the transition to the resistant dauer and promotes continued normal growth. The DAF-12 nuclear receptors are also found in other parasitic nematodes and are conserved in S. stercoralis (7), as are the dafachronic acid signaling molecules (8). Humans and mice are both initially infected by the third-stage S. stercoralis larvae (Fig. 1A, L3i), which penetrate the skin, often through uncovered feet. These L3i larvae migrate to the intestine, where they develop into adult females that reproduce parthogenically. In the intestine, females produce eggs that hatch and develop as first-stage larvae, also in the intestine. The L1 larvae (Fig. 1B) are then released and voided in the feces, or remain within the intestine to develop as L3a, autoinfective third-stage larvae that burrow into the large intestine to start a new cycle of infection within the same host. This self-infection, which is continuous, allows the S. stercoralis parasite infection to last for years if undetected. Unfortunately, if these infected people become immunosuppressed, for example by glucocorticoids or if they develop HIV/AIDS, the worms multiply and cause a hyperinfection, which is lifethreatening. The hyperinfection is characterized by increased parasite numbers, dissemination of the parasites to different regions and tissues of the body, along with a systemic distribution of gut bacteria (septicemia). Patton et al. (4), show that this human hyperinfection condition can be closely modeled in NSG immunocompromised mice when triggered by treatment with the glucocorticoid,methylprednisolone, and thatΔ7-dafachronic acid, an agonist of the DAF-12 nuclear receptor, limits the development of hyperinfection. Their observations are both remarkable and important because they illustrate the significance of a nuclear receptor in