Genetic and Evolutionary Analysis of Diethylcarbamazine Resistance in Parasitic Nematodes

Background

Nematode worms are among the most ubiquitous animals on earth. By some estimates, in terms of sheer numbers of individuals, nematodes account for 4 out of every 5 organisms on the planet (not counting bacteria and viruses). This remarkably diverse phylum contains free-living species that feed on bacteria, fungi, and other nematodes, and a large number that are parasites of insects, plants, and animals.

Worldwide, parasitic nematodes pose a major challenge to human health, livestock husbandry, and agriculture. Among the species that parasitize humans, the arthropod-transmitted ‘filarial' worms infect over 120 million people in 80 countries across the tropics and sub-tropics. These worms take up residence in the lymphatic system where they cause inflammation, edema, and massive obstruction of lymph flow in the arms, lower legs, and genitals. This debilitating condition, termed lymphatic filariasis [photos], exacts a toll in these regions exceeded only by that of malaria and tuberculosis.

Over the years, a number of drugs have been used to treat and prevent infection with filarial nematodes. In the same way that pathogenic bacteria have evolved resistance to many of our (overused) antibiotics, faced with similar selective pressures, filarial worms can be expected to do the same. In fact, high levels of resistance to Ivermectin, which for decades has been a mainstay anti-filarial drug, are increasingly being observed in worms that parasitize livestock.

Project Description

This project is aimed at exploring resistance to the anti-filarial drug diethylcarbamazine (DEC), which is used extensively to treat human populations worldwide. If resistance to DEC exists in any of these areas, molecular diagnostic assays capable of detecting this resistance, and its prevalence, would provide valuable baseline information for treatment and eradication programs. To this end, we are engaged in experiments aimed at elucidating the molecular genetic mechanisms of DEC resistance, and are generating molecular markers that can be used to discriminate between resistant and wild-type worms. At present, we are using the free-living nematode Caenorhabditis elegans as surrogate model; later work will adapt these tools to the real bad guys: Wuchereria bancrofti , Brugia malayi , B. timori , and others.