Investigating genetic composition of Onchocerca worms pre- and post-drug-treatment: Improving the ability to test macrofilaricidal drug efficacy
Community Directed Treatment with Ivermectin (Mectizan®) (CDTI) is the current World Health Organization (WHO) recommended method of controlling onchocerciasis caused by Onchocerca volvulus. However, ivermectin does not kill the adult worms, instead it targets microfilariae and temporarily affects the fecundity of adult female worms for a period of 6 to 12 months. New drugs are needed to eliminate the disease. Clinical evaluation of new drug candidates are being conducted in endemic areas where transmission continues. However, genetic techniques are required to successfully distinguish parasites which have survived treatment, from new infections. Through genotyping an infection, we aim to differentiate treatment failure from newly acquired infections which can act as a surrogate marker for parasitological cure. This rotation project will optimise and utilise whole genome sequencing methods to determine the genetic differences in O. volvulus microfilariae recovered from subjects before and after treatment. We will use O. volvulus microfilariae to accurately infer the adult worm populations, using genetic finger printing methods and sibship analysis of individual microfilariae. This will enable, for the first time, the accurate assessment of macrofilaricide/long term anti-fecundity drug efficacy in endemic areas, providing a method to distinguish drug failure (sibling or half-sibling parasites spread across pre- and post-treatment) from reinfection (parasites from genetically distinct parents).
A longer PhD project would expand on this work, utilising samples from animal infections across cattle skin hides to understand microfilariae geographical distributions across infected host skin, and the genetic diversities seen within and between hosts: Because of the long timeline and ethical and practical difficulties of obtaining microfilariae and adult worms from active human infections to optimise the techniques, further method and analysis development can be performed using the bovine-infecting sister species Onchocerca ochengi, before further studies in vivo O. volvulus to monitor existing anti-filarial drugs, and offer insight into the potential emergence and spread of drug resistance (i.e. resistance to existing drugs is predicted to be associated with diminished genetic variability in surviving worms post-treatment), as well as providing mechanistic insight into drug resistance, mating structures, parasite genetic diversity and potential future drug targets.
How can we best reduce transmission of Schistosoma mansoni?
Over 240 million people have schistosomiasis, a debilitating disease intrinsically linked to inadequate water, sanitation and hygiene (WASH). A wicked problem is a social or cultural problem that is difficult or impossible to solve. Despite extensive mass drug administration (MDA), schistosomiasis remains a wicked public-health problem. WASH-interventions are needed to reach the World Health Organization (WHO) 2030 goal of elimination as a public-health problem. Yet we don’t understand the full impact of schistosomiasis, and therefore cannot identify what feasible and cost-effective WASH interventions best reduce this impact, nor the threats to long-term control programme success, and how to mitigate these. We have an ongoing project that is addressing five key questions:
1. What are the true health, economic and societal impacts of schistosomiasis?
2. What are the most cost-effective combinations of WASH and MDA interventions?
3. How best can we scale-up these public-health WASH interventions to reach WHO 2030 goals?
4. What are the risks from human mobility to achieving and sustaining WHO 2030 goals?
5. How can cross-sectorial policy buy-in be leveraged to help reach these goals?
We use interdisciplinary methods to tackle this wicked public-health problem including: a bottom-up approach to identify acceptable, equitable, cost-effective, feasible, multifaceted interventions with highest ‘value for money’ and impact on schistosomiasis health-related quality of life; developing a field-based morbidity marker to monitor success; combining parasite genomics with mathematical models to inform on control programme endpoints; and identifying community, through to international level, facilitators to leverage for intervention success. A range of topics are available for a rotation project and/or subsequent PhD that can be linked with any of these questions, and focus on individual skillsets or interdisciplinary methods, student depending.