Plasmodium spp. (malaria) parasites remain one of the world’s most deadly infectious agents. The related parasite Toxoplasma gondii infects a third of the world’s population and likely contributes to chronic disease and causes severe and fatal infections during pregnancy. Through national/international collaborations and supported by competitive and industry funding, we are applying in vitro and in vivo approaches to identify and develop new drug and vaccines against malaria and Toxoplasma. We also explore their unique, and potentially druggable, adaptations that help them survive. 

Half of the world’s population is at risk of infection with mosquito-borne malaria parasites of the genus Plasmodium. These complex eukaryotic parasites that live inside human cells cause widespread sickness and death throughout tropical and sub-tropical regions of the world including countries neighbouring Australia. The majority of the >600,000 malaria related deaths that occur each year are caused by the parasite Plasmodium falciparum in children under 5 years in Africa, Asia and South America. Unfortunately, resistance has developed to our most effective anti-malarial drugs, resulting in poorer treatment outcomes for clinical cases of this deadly parasite. In the case of T. gondii, which infects wildlife, livestock and up to a third of the worlds human population, we are reliant on old drugs of questionable efficacy. There is an urgent need to identify novel drugs to partner with current first-line treatments to fill these treatment gaps. In addition, development of effective vaccines would reduce the burden of disease and greatly facilitate efforts to eradicate malaria and control T. gondii infection. Unfortunately, a highly effective vaccine to protect against malaria or T. gondii has not been developed to date and efforts to identify the best vaccine targets are ongoing.

Antimalarials that inhibit invasion and parasite growth

My laboratory seeks to identify and characterise novel parasite proteins for their suitability as both drug and vaccine targets. We look at drugs that block invasion of the human red blood cell by the small invasive merozoite stage of the malaria parasites lifecycle as a therapeutic target. We also work with small molecule and natural products that inhibit malaria parasite or T. gondii growth at nanomolar concentrations as potential new tools to investigate biology and for clinical development.

By applying state of the art methods, we aim to develop anti-malarial and anti-Toxoplasma drugs that can be used to partner or replace current frontline treatments. Using a breakthrough P. falciparum merozoite purification method (PNAS, 2010; Figure 1) and a highly reproducible flow cytometry approach (Antimicrobial Agents & Chemotherapy, 2013; Figure 2 A & B), we have screened traditional antimalarial therapies, protease inhibitors, kinase inhibitors, a range of antibiotics and identified several compounds and there analogues that rapidly inhibit merozoite invasion (BMC Biology, 2015). Using standard in vitro assays, we have also screened several thousand small molecules and natural products for their broad spectrum activity against malaria parasites and Toxoplasma gondii. To understand how drug-like compounds kill the parasites, we apply mutation analysis of gene targets, phenotypic screens of related Apicomplexan parasites, modifications and screens of analogues, fluorescence microscopy localisation and proteomic identification of drug binding targets. Importantly, many of the invasion inhibitory compounds identified in our research also kill at other stages of the parasites complex lifecycle, increasing their utility as broad acting antimalarials. Development of both invasion inhibitory and broad acting compounds and identification of the mechanisms by which they inhibit invasion is the subject of ongoing research in the laboratory.

Functional characterisation of essential malaria proteins and vaccine targets

The function of nearly 50% of the genes in P. falciparum parasites is poorly described or not known altogether. Malaria proteins involved in invasion are no exception with a large number of potential vaccine and drug targets having no known function. We apply gene-editing techniques to examine the potential role of some of these proteins in invasion and parasite growth. Using fluorescence microscopy (Figure 3), flow cytometry, genetic manipulation and proteomic techniques, we are characterising the localisation, interactions and functions of merozoite antigens with no known function to test their suitability as therapeutic targets. 

Postgraduate and undergraduate opportunities

Honours, summer-student, masters and PhD projects are available to explore the biology of the malaria parasite and to develop new therapies against this deadly infectious organism. We are a small, supportive, research team that is applying new technologies to discover new ways of ending the burden of malaria disease. If you would like to find out more about our current research opportunities and whether our research is right for you, please contact Dr. Danny Wilson (danny.wilson@adelaide.edu.au).