Filarial diseases are life-long conditions affecting ~150 million people. Current control programmes target the transmissive stage of filariae but are not effective at directly killing adult parasites. Governmental and major private philanthropic stakeholders have recognised that the development of a curative drug holds the promise of eliminating filariasis as a public health problem. Pre-clinical testing of novel therapeutics need to be undertaken both directly against filarial parasites in vitro and in the context of a whole animal pathophysiological setting (in vivo). There is currently no system to generate filariae outside of the body, meaning that a rodent host (Mongolian gerbil) is required to be infected to produce adult lymphatic filariae. For onchocerciasis, no small animal model exists and only cattle naturally or experimentally infected with related bovine onchocerca can be used to screen drugs. Similarly, for loiasis, no small animal model has been developed. The available model is the use of splenectomised baboons. Large animals naturally susceptible to lymphatic filariae (cats and dogs) are also used in drug testing. This studentship will define whether animal usage in filariasis drug testing can be reduced by:
(I) assessing whether co-cultures of human lymphatic endothelium and lymphocyte cell lines can propogate adult filariae from larvae in vitro, thus replacing gerbils which maintain the life cycle and to generate parasites for ex vivo testing.
(II) evaluating whether cattle onchocerca nodules containing adult worms can be implanted into severe-combined immunodeficiency (SCID) mice and survive for sufficient time to assess drug testing, thus replacing cows as an onchocerciasis drug screen.
(III) undertaking experimental infections with Loa loa larvae in SCID mice to evaluate whether these mice are permissive to patent infection and can replace primate models.
(IV) exploring bioimaging techniques to refine endpoint efficacy measurements.
Marriott A et al. (2019). Validation of ultrasound bioimaging to predict worm burden and treatment efficacy in preclinical filariasis drug screening models. Scientific Reports 8:5910. doi: 10.1038/s41598-018-24294-2
Taylor M et al. (2019). Preclinical development of an oral anti-macrolide drug for the treatment of lymphatic filariasis and onchocerciasis. Science Translational Medicine 11(483). doi: 10.1126/scitranslmed.aau2086
Zofou D et al. (2018). Evaluation of in vitro culture systems for the maintenance of microfilariae and infective larvae of Loa loa. 11(1):275. doi: 10.1186/s13071-018-2852-2