Disrupting a worm's life cycle could be the key to ending parasitic infection.

Strongyloides parasites increase their metabolism and express a whole new set of genes once they've entered the host.

The trick to killing roundworms—such as hookworms and threadworms, which infect humans—may be to force the parasites to grow up too quickly. HHMI investigator David J. Mangelsdorf discovered that the molecular pathway governing how the harmless roundworm Caenorhabditis elegans exits a hibernation state controls the transition between life stages in many parasitic worms. He's figured out a way to intervene in that pathway and kill larvae—something existing drugs can't do.

In 2006, Mangelsdorf's team at the University of Texas Southwestern Medical Center at Dallas identified molecules—dafachronic acids—that bind to DAF-12, a receptor involved in C. elegans longevity. They found that the receptor is a checkpoint for worms exiting dauer diapause—a dormant state that C. elegans larvae enter when they perceive low temperature, crowding, or a lack of food. When the worms sense more favorable times, they produce dafachronic acids, which activate DAF-12, ending dauer diapause by turning on genes involved in reproduction and food metabolism.

Mangelsdorf's group has now shown that the parasitic worm Strongyloides stercoralis, among others, also has DAF-12. While these parasites don't enter dauer diapause, they do go through a similar dormant stage. So-called stage 3 infective larvae (iL3) keep their metabolism low until they sense a friendly environment inside a host. Taking hints from the C. elegans pathway, Mangelsdorf and his collaborators treated the iL3 parasites with dafachronic acid. It forced the worms out of their infectious state but not fully into the next life cycle stage—the worms died before they could reproduce, the team reported in a Proceedings of the National Academy of Sciences article that appeared online on June 2, 2009.

The current drug of choice to kill S. stercoralis targets adult parasites—eggs and larvae inside the host remain viable. Using dafachronic acid to force larvae out of their infectious state and kill them could end the hard-to-stop cycle, says Mangelsdorf. His lab is screening synthetic compounds for drugs that could mimic dafachronic acid's effects and is looking more closely at the biochemical pathways that DAF-12 controls.

Photo: Dr. Mae Melvin / CDC Public Health Image Library