Date Published: February 20, 2015
Publisher: Public Library of Science
Author(s): Christina A. Bulman, Chelsea M. Bidlow, Sara Lustigman, Fidelis Cho-Ngwa, David Williams, Alberto A. Rascón, Jr, Nancy Tricoche, Moses Samje, Aaron Bell, Brian Suzuki, K. C. Lim, Nonglak Supakorndej, Prasit Supakorndej, Alan R. Wolfe, Giselle M. Knudsen, Steven Chen, Chris Wilson, Kean-Hooi Ang, Michelle Arkin, Jiri Gut, Chris Franklin, Chris Marcellino, James H. McKerrow, Anjan Debnath, Judy A. Sakanari, Robin B. Gasser. http://doi.org/10.1371/journal.pntd.0003534
Abstract: Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s) of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.
Partial Text: River blindness and lymphatic filariasis (LF) are two major neglected diseases caused by filariid nematodes that, together, affect an estimated 145 million people worldwide in mostly poor, developing countries [1,2]. River blindness, caused by the filariid nematode Onchocerca volvulus, is a chronic, debilitating disease and a major cause of infectious blindness. The adult worms, or macrofilariae, reside in subcutaneous tissues where females release the early larval stage, microfilariae, into the skin. Adult worms can reproduce for up to 10–14 years, releasing millions of microfilariae over an infected individual’s lifetime . Microfilariae migrate throughout the tissues and those that accumulate in the eyes induce an inflammatory response that eventually leads to blindness . LF is caused by several species of filariid nematodes: Wuchereria bancrofti, Brugia malayi and B. timori. The adult worms reside in the lymphatic tissues where females release microfilariae into the circulation. The microfilariae are then ingested by mosquitoes and develop into the infectious larval stage. With LF, the chronic condition is characterized by pain and severe lymphedema often involving the arms, legs, breasts and genitalia, as well as elephantiasis, all of which may lead to social stigma and economic loss to those afflicted [4,5].
The main goal of our study was to identify macrofilaricidal drugs for the treatment of onchocerciasis and LF. Two major challenges in developing new drugs for these neglected diseases are finding suitable animal models for preclinical studies and limiting the costs of drug development and production. To date, the only animals in which O. volvulus can develop to patency are chimpanzees and mangabey monkeys [34–36]. O. ochengi, which infects cows, is thought to be closely related to O. volvulus , and previous studies have used O. ochengi as a model for O. volvulus infection [13–15]. Brugia malayi and B. pahangi, as members of the Filariidae family, are also closely related to O. volvulus . Because of the large number of compounds required to identify preclinical candidates and with the accessibility of large numbers of adult worms that can be collected from gerbils, we selected adult Brugia for our primary screens. Following our funneling scheme, we first identify compounds screened with adult female Brugia in the Worminator assays. Compounds that inhibit motility by 75% compared with control worms are then screened against O. volvulus molting larvae and O. ochengi adult worms in an MTT assay and motility assay.