Nuclear receptors in parasitic nematodes

Introduction One of the most prevalent classes of parasitic organisms is the helminth (parasitic worms), which collectively infect more than 1 billion people worldwide and cause a range of maladies including malnutrition, growth and mental retardation, disfigurement and physical disabilities, and death (1). Helminths that infect humans are generally considered to comprise two major phyla: Nematoda (round worms), both soil-transmitted and filarial; and Platyhelminthes (flatworms), both flukes and tapeworms. Parasitic worms represent one of the most successful and diverse extant forms of life. For example, of the 40,000 or more presumed nematode species, it is estimated that over half are parasitic (2). There also are believed to be more than 15,000 species of flatworm parasites. Mammalian parasites that are transmitted orally or through the skin from food or soil contaminated with eggs or young larvae usually colonize host intestines. Filarial parasites that are transmitted from biting insect vectors such as black flies or mosquitos enter the definitive host when the vector takes a blood meal. Filarial parasites infect a variety of different human tissues, with tissue specificity determined by the individual species (1). Unfortunately, few therapies exist to treat these parasites, and the long history of extensive use of anthelmintic drugs has resulted in a growing rate of resistance, which is now pervasive in nematode parasites infecting livestock (3). In the absence of alternative therapeutic strategies (e.g., vaccines), novel drugs to treat these infections are urgently needed. Nuclear receptors are ligand-gated transcription factors that regulate diverse biological processes, including metabolism, development, and reproduction (4). Because of the lipophilic nature of their ligands and their ability to modulate the expression of multiple genes within the same pathway, nuclear receptors have become attractive targets for the development of orally available small-molecule drugs (4). Importantly, nuclear receptors have been identified in all categories of helminths (see ref. 5 for a systematic review of nuclear receptors found in helminths). We propose that targeting nuclear receptors would provide a novel therapeutic strategy that is distinct from current anthelmintic drugs, which target tubulins (benzimidazoles), ion channels (ivermectin and diethylcarbamazine), or symbotic bacteria of parasites (doxycycline). Here we review the current data suggesting nuclear receptors may be effective drug targets for treating helminthic diseases.