Plasmodium Knowlesi As A Genetic Model For Plasmodium Vivax Drug Resistance
Funder
National Health and Medical Research Council
Funding Amount
$417,193.00
Summary
Two different Plasmodium parasites cause the majority of malaria worldwide. However, one type, P. vivax, is unable to be cultured in the laboratory and therefore has been poorly studied. Drug resistance has been observed but the underlying causes are poorly understood. We propose to use a closely related parasite, P. knowlesi, as a model to understand drug resistance mechanisms. This knowledge will be used to follow resistance in the field and direct policy of the most appropriate treatment.
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.
Chloroquine Resistance And The Physiology Of The Malaria Parasite S Digestive Vacuole
Funder
National Health and Medical Research Council
Funding Amount
$287,921.00
Summary
Malaria is an infectious disease, caused by a single-celled parasite which invades the red blood cells of its human host. Each year, malaria causes the death of up to 3 million people, mostly children under the age of 5 The parasite has become resistant to most, if not all, of the antimalarial drugs presently available, and there is no vaccine. There is therefore an urgent need to develop new antimalarial drugs, and-or to devise strategies for overcoming the parasite s drug resistance mechanisms ....Malaria is an infectious disease, caused by a single-celled parasite which invades the red blood cells of its human host. Each year, malaria causes the death of up to 3 million people, mostly children under the age of 5 The parasite has become resistant to most, if not all, of the antimalarial drugs presently available, and there is no vaccine. There is therefore an urgent need to develop new antimalarial drugs, and-or to devise strategies for overcoming the parasite s drug resistance mechanisms. Chloroquine was, for many years, the mainstay of antimalarial chemotherapy and was, in many senses, a 'wonder-drug' cheap, safe and effective. However the emergence and spread of parasites that are resistant to chloroquine has meant that the drug is now largely useless as an antimalarial. Chloroquine kills (sensitive) parasite through an effect on the parasite s digestive vacuole an internal acidic compartment in which the parasite breaks down protein taken up from its host red blood cell. This compartment plays a crucial role in the growth and proliferation of the parasite. Yet we understand very little about its basic physiology, and nor do we understand the mechanism by which chloroquine-resistant parasites are able to survive exposure to the drug. The aim of the work proposed here is to gain an increased understanding of some of the mechanisms underlying the physiology of the parasite s digestive vacuole, as well as some of the factors influencing the accumulation of chloroquine within this compartment. The former part of the work may well reveal new antimalarial drug targets. The latter part of the work will increase our understanding of the mechanism of chloroquine resistance, thereby laying the groundwork for strategies by which these mechanisms might be circumvented and chloroquine-related drugs thereby restored to the front-line of our ongoing and increasingly desperate fight against malaria.Read moreRead less
The Na+-H+ Exchanger And H+-pumping Pyrophosphatases Of The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$664,604.00
Summary
Malaria is an infectious disease caused by a single-celled parasite. The disease kills up to 2 million people each year and the parasite is becoming increasingly resistant to available drugs. This work focuses on the mechanisms by which the parasite controls its internal ion concentrations. These mechanisms may be new drug targets, and they may also play a role in antimalarial drug resistance. For both of these reasons it is important that we understand them.
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