More than 120 million of poorest in the world are at high risk of suffering the debilitating effects of the parasitic filarial nematodes? Wuchereria bancrofti, Brugia malayi, and B. timori ? that live in the lymphatic system and cause human lymphatic filariasis, commonly known as elephantiasis, as well as other severe pathologies. Onchocerciasis (river blindness), for one, is caused by Onchocerca volvulus, which resides within subcutaneous nodules and releases the microfilariae (Mf) that are responsible for ocular or dermal pathologies, including blindness. International control programs, which target 1.5 billion people in danger of infection, focus on controlling the transmission of infections. Unfortunately, the treatments used for mass drug administration initiatives (ivermectin) produce only microfilaricidal effects ? they block transmission but have no effect on the adult parasites. They also require long-term yearly administration, are contraindicated in areas co-endemic with Loa loa, exempt children and pregnant women, and promote drug resistance in filarial nematodes. Together, these limitations point to a crucial need for the development of new anti-filarial drugs, specifically macrofilaricidal drugs that kill adult worms. Recent data demonstrate the unique potential of using Wolbachia, the mutualistic bacteria of filarial nematodes, as a novel chemotherapeutic target against human filarial infections. Clinical studies showed that the administration of antibiotics (doxycycline) kills endosymbionts and causes macrofilaricidal effects. To explore this potential, we introduce a novel approach: a host(parasite)- oriented treatment that induces a host innate defense and forces filarial nematodes to eliminate their endosymbiont. We intend to take advantage of autophagy, a mechanism of eukaryotic cells to maintain a healthy intracellular environment and protect cells against intracellular invaders (e.g., bacteria, virus es). The process is essential for bacteria-filaria symbiosis and its alteration killed Wolbachia and, consequently, the worm itself. We obtained proof, that niclosamide (autophagy inducer) activates autophagy in parasites, significantly decreases number of bacteria and causes embryostatic effect in adult worms. Our project will determine that the autophagy inducers can be candidate macrofilaricidal drugs.
In Aim 1, to prove that autophagy inducers are effective in vivo against filarial parasites and can be used as macrofilaricidal drugs, we will evaluate the efficacy of niclosamide in Brugia infected jirds. In parallel, we will test the other 23 repurposed drugs (known autophagy inducers) on adult Brugia parasites in vitro and compare their effects on the Wolbachia load and adult worm fitness. The in vitro assays in Aim 1 will result in the selection of the best hits (even better than niclosamide).
In Aim 2, the best 2 candidates will be validated in our in vivo Brugia/jird model of infection. Our end goal is to identify effective new microfilaricides that interfere with symbiosis. This initiative, we believe, will yield a new class of active compounds and open perspectives for repurposed drugs, for use as alternatives to or in combination with current anti-filarial treatments.

Public Health Relevance

Major global initiatives sponsored by the World Health Organization and other agencies focus on controlling human filarial parasite transmission, with the ultimate goal of eliminating lymphatic filariasis use the drugs that have only microfilaricidal effects for the mass drug administration. Filarial parasites have evolved a mutualistic association with endosymbiotic bacteria, Wolbachia, which the worms need to develop, grow, and survive; and recent data have demonstrated the unique potential of using Wolbachia as a novel chemotherapeutic target against adult parasites (macrofilaricidal effect). Our bold idea of this project is to employ a parasite-oriented treatment that induces nematode innate defense to disturb Wolbachia-parasite symbiosis affecting the survival of the adult parasites and its own symbiont.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI153649-01
Application #
10040523
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcgugan, Glen C
Project Start
2020-06-19
Project End
2022-05-30
Budget Start
2020-06-19
Budget End
2021-05-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
New York Blood Center
Department
Type
DUNS #
073271827
City
New York
State
NY
Country
United States
Zip Code
10065