Anti-Wolbachia therapy as a new approach to prevent zoonotic filariases

Veterinary zoonotic filariases are emergent vector-borne diseases caused by Brugia malayi, Dirofilaria immitis & D. repens infections of cats and dogs. Cats act as a reservoir host of human lymphatic filariasis (LF) in Asian foci which threatens the successful elimination of LF as a public health problem. Cats and dogs are also at risk of developing life-threatening disease when infected with the heartworm, D. immitis, and humans can acquire dirofilariasis invoking pulmonary and permanently damaging ocular pathologies. The incidence of dirofilariasis in animals is under-appreciated in the tropics but is spreading through North-West Europe and America due to global heating and establishment of invasive mosquito species. The current strategy to control human zoonotic filariases is via regular preventative treatment of pets with macrocyclic lactones, such as ivermectin. Once an animal becomes chronically infected, macrocyclic lactones or melarsomine are therapies aimed at long-term suppression of microfilaraemias or cure, respectively. Current issues with these treatments are emergence of drug resistance, drug toxicity and risk of severe inflammatory adverse reactions following rapid killing of large adult parasites in lymphatic or pulmonary vasculatures. A new approach to cure and/or prevent veterinary filariases is via targeting the filarial endosymbiont, Wolbachia. We have recently developed a new ‘fast-acting’ anti-Wolbachia azaquinazoline drug class with a clinical candidate progressing through clinical trials. Further, we have identified pharmacological synergy when combining a variety of registered anti-Wolbachia drugs with certain classes of registered anthelmintics, with further treatment-shortening impact.

In this project you will research the exciting potential of our novel azaquinazoline anti-Wolbachia investigational drugs as effective preventative and curative therapies for veterinary zoonotic filariasis utilising a variety of in vitro, ex vivo and in vivo advanced preclinical models. Research aims will include:

 

  • Determine minimal chemotherapeutic regimens and systemic exposures of investigational azaquinazoline anti-Wolbachia drugs which mediate prophylaxis or cure, including against macrocyclic lactone resistant isolates of Dirofilaria
  • Explore synergism when combining with macrocyclic lactones or other anthelmintic combinations
  • Identify mode-of-action underpinning drug combination synergy
  • Work with industrial and potential field partners to test curative regimens in infected cats or dogs

 

T2 Human / Clinical Research

T1 – Basic Research

Expected Outputs

High impact research publications

Potential intellectual property filing and product development opportunities via industrial partnership

Potential for impact: commercialisation, working with industry, development of a new therapy for prevention and control of veterinary zoonotic filariasis

Training Opportunities

Whole animal physiology

Parasitology

Cell culture

Molecular biology

Informatics

Biochemistry

Skills Required

A grounding in parasitology and/or molecular biology is important Skills with data analysis using STATA, R, or similar package

Key Publications associated with this project

Johnston, K. L. et al. Anti-Wolbachia drugs for filariasis. Trends Parasitol (2021) doi:10.1016/j.pt.2021.06.004.

Turner, J. D. et al. Novel anti-Wolbachia drugs, a new approach in the treatment and prevention of veterinary filariasis? Veterinary Parasitology 279, 109057 (2020).

Hong, W. D. et al. AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis. Proceedings of the National Academy of Sciences of the United States of America 10, 201816585 (2019).

Turner, J. D. et al. Albendazole and antibiotics synergize to deliver short-course anti- Wolbachia curative treatments in preclinical models of filariasis. Proceedings of the National Academy of Sciences 8, 201710845–10 (2017).

Halliday, A. et al. A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis. Parasites & Vectors 7, 472 (2014).

LSTM Themes and Topics – Key Words

Neglected Tropical Diseases

Tropical Disease Biology Drug Discovery & Development

CLOSING DATE FOR APPLICATIONS:

Application Portal closes: Thursday 9th February 2023 (12:00 noon UK time)

Shortlisting complete by: End Feb/early March 2023

Interviews by: Late March/early April 2023

Further information on the MRC CASE/DTP 2023/24 programme and how to apply can be found here