Role Of Plasmepsin V And PTEX Complex In Plasmodium Liver Infection
Funder
National Health and Medical Research Council
Funding Amount
$848,408.00
Summary
Plasmepsin V and PTEX are essential proteins for malaria parasites to grow inside red blood cells. These proteins control the export of parasite proteins into red cells, causing disease. Before red blood cells are infected, parasites invade liver cells. Plasmepsin V and PTEX are expressed during liver infection but their function is currently unknown. We hypothesise that they allow parasites to export proteins into liver cells in order to survive and, thus, are antimalarial drug targets.
Identifying Metabolic Pathways In Leishmania Parasites And Their Host Cells Required For Virulence
Funder
National Health and Medical Research Council
Funding Amount
$989,110.00
Summary
Our lack of understanding of microbial metabolism in infected animal tissues has hindered the development of effective therapies. This is particularly true for many parasitic diseases, including Leishmania spp that cause devastating disease throughout the tropics. We will utilize a range of innovative analytical and genetic approaches to identify metabolic pathway in Leishmania parasites and infected host cells that are required for virulence and are potential drug targets.
Interdisciplinary Insights Into The Rational Design Of Malaria Therapy And Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Malaria is a global health concern with almost half a million deaths annually. There is an urgent need for a highly effective malaria vaccine and new antimalarials. However, despite decades of research into this pathogen, our understanding of what causes illness in a person and how immunity operates is limited. This project will use a mathematical modelling approach to provide a new way to understand infection, as a rapidly changing and intricate process.
Plasmodium vivax is a parasite that invades the youngest of human red blood cells. Our work will reveal how this malaria parasite enters our blood cells and the molecular mechanisms that allows successful invasion. This proposal will redefine our understanding of P. vivax invasion and explore novel ways to block its entry into red blood cells and therefore prevent malaria infection.
Transport Pathways Of Host-derived Iron In Schistosomes Parasites
Funder
National Health and Medical Research Council
Funding Amount
$322,091.00
Summary
This project will identify the diversity and biological roles of receptors for metabolic iron expressed on the body surface of the parasitic blood flukes (schistosomes) of humans. Schistosomes are a major health problem in many tropical countries and are responsible for significant human morbidity and lost productivity. Adult worms feed on human blood, from which derive amino acids for the production of many hundreds of eggs released per day into the human blood stream. The intense cellular resp ....This project will identify the diversity and biological roles of receptors for metabolic iron expressed on the body surface of the parasitic blood flukes (schistosomes) of humans. Schistosomes are a major health problem in many tropical countries and are responsible for significant human morbidity and lost productivity. Adult worms feed on human blood, from which derive amino acids for the production of many hundreds of eggs released per day into the human blood stream. The intense cellular response induced by parasite eggs trapped in body organs is the major cause of chronic human disease. We have discovered two intriguing phenomena of iron metabolism in schistosomes. Firstly, schistosomes have a greater reliance on iron than many other organisms, storing a surfeit in cells that produce the protein-rich egg shell. Secondly, a major transmembrane iron transporter of the parasites, thought to be involved in the uptake of iron, is found on the parasite external body surface and not in the parasite intestine. The extensive nutritional dependence of these worms on iron and the surface location of mediators of iron uptake raise the exciting possibility that we have uncovered a novel system that might be exploited for vaccine or drug-mediated control of these significant human parasites. If we can dissect the pathways schistosomes use to derive iron from their hosts, we may be able to generate vaccines to block this nutritional pathway, or use drugs to block embryogenesis. This project is a fact-finding mission that asks if the host-interactive tegument of these parasites is a major source of metabolic iron. Molecules we demonstrate to be present on the surface will be tested as vaccine candidates in mouse vaccine trialsRead moreRead less
Proteasome Inhibitors As Reversers Of Resistance To Artemisinin-based Antimalarials
Funder
National Health and Medical Research Council
Funding Amount
$473,534.00
Summary
Current antimalarial control is highly dependent on Artemisinin Combination Therapy (ACTs), which makes recent reports of decreased clinical efficacy of artemisinins extremely concerning. This project will develop proteasome inhibitors to synergise the activity of artemisinins - effectively reversing resistance. We will confirm that the selected compounds have good bioavailability, low cytotoxicity in human cell lines and efficacy in mouse models of malaria.
Activation of invasion in Toxoplasma. Host cell invasion is critical for the establishment and maintenance of infection by the single-celled parasite Toxoplasma gondii, the causative agent of Toxoplasmosis. This project will use the latest molecular techniques to understand how invasion is activated and will define a new set of drug targets to treat Toxoplasmosis and related diseases.
Functional proteomics of Giardia. This project will use the latest tools for dissecting and comparing genes and their protein products from one of the most common parasites infecting people, their pets, livestock and wildlife. This protozoan parasite Giardia is also of evolutionary and biological significance in terms of understanding the origin of higher animals from bacteria as well as fundamental questions about the parasitic way of life. Giardia proteins will be identified and characterised ....Functional proteomics of Giardia. This project will use the latest tools for dissecting and comparing genes and their protein products from one of the most common parasites infecting people, their pets, livestock and wildlife. This protozoan parasite Giardia is also of evolutionary and biological significance in terms of understanding the origin of higher animals from bacteria as well as fundamental questions about the parasitic way of life. Giardia proteins will be identified and characterised on the basis of their value in understanding disease processes and treatment, and by working with appropriate industry partners, proteins of commercial value will be exploited.Read moreRead less
Interactions Between The Malaria Parasite's Chloroquine Resistance Transporter And Antimalarial Drugs
Funder
National Health and Medical Research Council
Funding Amount
$485,641.00
Summary
The malaria parasite is a single-celled organism which invades the red blood cells of its host. The aim of this project is to characterize the parasite protein responsible for conferring resistance to chloroquine, and to study its interaction with other antimalarial drugs. The parasite's susceptibility to chloroquine, and other drugs, is altered by small changes in this protein. This work will advance our understanding of the increasingly widespread phenomenon of antimalarial drug resistance.
Developing Synergisers Of The Antimalarial Drug, Chloroquine, For The Treatment Of Chloroquine-resistant P. Falciparum.
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselve ....Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselves, can synergise the action of chloroquine. This may involve the inhibition of the activity of proteins that directly or indirectly extrude chloroquine from its site of action in the parasite's digestive apparatus. Unfortunately, thechloroquine synergisers examined to date have been too toxic to be useful in vivo. In preliminary studies we have identified some compounds that would be suitable for use in malaria patients, including a widely used antimalarial drug, primaquine, that can synergise the activity of chloroquine against chloroquine-resistant parasites. We will attempt to understand the molecular basis of this interaction. This will allow us to define optimal combinations of chloroquine and a resistance-reversing quinoline for use treating malaria. This could extend the clinical life of this important antimalarial drug. The information obtained may also help to design novel antimalarial drugs.Read moreRead less