Drugs and Targets to Perturb the Symbiosis of Wolbachia and Filarial Nematodes

Abstract

A novel approach to the treatment of filarial nematodes has been to target the Wolbachia bacterial endosymbionts, which are essential for nematode development, embryogenesis, and survival. A 4- to 6-week course of doxycycline (200 mg/kg/day) results in the long-term sterility and ultimate death of the adult parasite. In addition to its potent antiparasitic effects, doxycycline therapy reduces the severity of clinical disease (hydrocele and lymphedema). The therapeutic effect of targeting Wolbachia on microfilariae and adult worms is slow and prolonged, delivering a good safety profile while both avoiding parasite- or Wolbachia-mediated inflammatory adverse reactions, and producing a sustained interruption of transmission. The use of doxycycline in widespread community-based control is compromised by the logistics of lengthy courses of treatment, and contraindications in children and pregnant women. To overcome these barriers, the Anti-Wolbachia Consortium (A·WOL), was established to optimize current regimens, and discover and develop new anti-Wolbachia drugs to deliver therapy compatible with mass drug administration (MDA) approaches. The potent sterilizing and macrofilaricidal activity of antiwolbachial therapy would greatly reduce MDA program timeframes, which may be required in regions where sustained delivery is problematic or in the event of reduced efficacy of currently used drugs. A·WOL has established screening approaches to exploit focused anti-infective and diversity-based libraries of existing and novel drugs and natural products. Target discovery has ranked essential genes to guide library selection and selected key pathways and enzymes thought to be involved in the symbiotic relationship for small-molecule library screening. Antiwolbachial therapy has become the most effective way to treat individuals with onchocerciasis and lymphatic filariasis, and the hope is that A·WOL can deliver a new generation of drugs and regimens needed to ensure the elimination of onchocerciasis and lymphatic filariasis.