Characterisation of Plasmodium falciparum (Malaria) therapeutic targets
Half of the world’s population is at risk of infection with the mosquito-borne
malaria parasite, Plasmodium falciparum. This includes those living in many
countries in Australia’s neighbouring Asia Pacific region. P. falciparum malaria
results in nearly 600,000 deaths each year, mainly 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. There is an urgent need to identify novel drugs to partner with current
first-line treatments to fill this looming treatment gap. In addition, development
of an effective vaccine would reduce the burden of disease and greatly facilitate
efforts to eradicate malaria. Unfortunately, a highly effective vaccine to protect
against malaria has not been developed to date and efforts to identify the best
vaccine targets are ongoing.
Our laboratory seeks to identify and characterise novel parasite proteins for
their suitability as both drug and vaccine targets. We focus on invasion of the
human red blood cell by the small invasive merozoite stage of the parasite
lifecycle as a therapeutic target. By developing therapeutics that inhibit
merozoite invasion of the red blood cell we can instantly disrupt the lifecycle of
the parasite in the stage that causes all the symptoms of the disease. Two main
areas of interest are available for you to explore in the laboratory.
1) Identification of novel drug-like inhibitors of merozoite invasion.
This project applies a ground-breaking method for the purification of malaria
merozoites, a technique developed by Boyle & Wilson et al., (PNAS, 2010), for the
characterisation of invasion proteins and their inhibitors (Wilson et al. BMC
Biology 2015; Wilson et al. Anti-Microbial Agents and Chemotherapy, 2013;
Riglar and Richard et al., Cell Host and Microbe, 2011). Using the merozoite
purification technique and flow cytometry based methods to measure invasion
inhibition, you will screen a library of antimalarial compounds and identify novel
inhibitors of merozoite invasion. The activity of lead inhibitors will then be
defined in detail, including characterisation of inhibitory phenotypes using flow
cytometry, fluorescence microscopy and genetic manipulation of potential drug
targets. This project could be the starting point for the development of novel
drugs to treat malaria.
2) Characterisation of the function of poorly defined proteins in invasion.
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 targets having no known
function. We have developed a number of transgenic parasite lines to examine
the potential role of some of these proteins in invasion and parasite growth.
Using fluorescence microscopy, flow cytometry, genetic manipulation and
proteomic techniques, you will characterise the proteins role in merozoite
invasion of the host red blood cell and parasite growth, determine its localisation
and explore potential protein binding partners. This project will uncover the role
of poorly characterised proteins in invasion, allowing a thorough assessment of
their suitability as therapeutic targets.
During the course of the year, both projects may give you the opportunity to
become familiar with:
i)
ii)
iii)
iv)
v)
culture of malaria parasites and purification of their lifecycle stages
(in particular the invasive merozoite stage)
design, cloning and transfection of malaria transfection vectors
immunofluorescence microscopy leading to localization of proteins
standard molecular biology and protein characterization techniques
and
proteomic analysis of protein binding partners
Expressions of interest should be directed to Dr. Danny Wilson
danny.wilson@adelaide.edu.au