DAF-12: A Novel Drug Target in Parasitic Nematodes

The nuclear receptor DAF-12, first identified in C. elegans, controls nematode species' entry into and exit from metabolically hypoactive resting states. In all of the parasitic species studied thus far, that resting state is the infectious third larval (iL3) stage, and activation of the receptor in iL3 worms outside of the host induces a premature and lethal molt (Wang et al. 2009; Motola et al. 2006). In contrast, the relatively uncontrolled soybean parasite Heterodera glycines, which causes USD 1 billion of crop damage annually in the U.S. (Wrather and Koenning 2006; Davis and Tylka 2005), does not go through an iL3 stage but rather arrests as the preinfectious second juvenile (piJ2) within the egg (Davis and Tylka 2005). However, just as iL3 worms only molt to L4 when they are inside their host (Wang et al. 2009), H. glycines nematodes only hatch as infectious J2s when they are near the plant roots required to support their development (Davis and Tylka 2005). This work demonstrates the importance of the DAF-12 ortholog in H. glycines for regulating hatching and introduces the the first well-defined molecular target for controlling the spread of this important pathogen. Additionally, an ortholog with significant sequence and likely functional similarity is identified in the related parasite Globodera pallida, which causes an identical disease in other major agricultural crops including potato and tomato plants and exhibits the same arrest phenotype inside the egg as H. glycines. Finally, a DAF-12 ortholog is cloned from Onchocerca gutturosa, one of several species in the Onchocerca genus that causes the disease onchocerciasis in both humans and livestock. Importantly, since onchocerciasis continues to elude the eradication efforts of several well-funded international programs, both an existing agonist and an avenue to identify endogenous agonists for the receptor are identified. These studies offer direction for the development of novel therapeutics to control these socially and economically important pathogens.