The Quinoline Antimalarials: Mechanisms Of Action And Resistance In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
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 these antimalarials so that replacement drugs can be designed. We propose to test the hypothesis that chloroquine acts by interfering with the detoxification of the by-products that are produced when the parasite f ....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 these antimalarials so that replacement drugs can be designed. We propose to test the hypothesis that chloroquine acts by interfering with the detoxification of the by-products that are produced when the parasite feeds on haemoglobin. We propose that the parasite develops resistance to chloroquine by excluding either the drug or the toxic by-products from the site of action. We further propose that proteins of the digestive vacuole of the parasite are involved in the development of resistance to chloroquine. We plan to identify and characterise these proteins and to use this information to design novel antimalarial drugs.Read moreRead less
Effector Export In P. Falciparum Infected Human Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$1,066,920.00
Summary
We will investigate malaria, a parasitic disease that kills over 450,000 people a year. We will explore how the parasite identifies, invades and remodels the host cells in which it lives, scavenging nutrients and hiding from the immune system. We will characterize the proteins involved in these critical events, as they are potential targets for drugs. We will study how parasites cause disease and how the host responds to infection.
Unravelling The Tetraspanin Web In The Schistosome Tegument.
Funder
National Health and Medical Research Council
Funding Amount
$309,537.00
Summary
Infection with the human blood fluke, Schistosoma mansoni, is a major human ailment affecting almost 200 million people world wide and causing approximately 200 000 deaths per year. Current control efforts rely on anthelminthic drugs but, to sustain their effects, they must be applied for an indefinite period of time due to reinfection. This project will extend recent efforts to develop a vaccine for this organism and decrease the public health burden and mortality associated with infection.
Schistosomes are parasitic flukes that survive in the blood vessels of their human hosts for many years. More than 200 million people are infected in developing countries, and Australian travelers to these regions are often infected. As larval schistosomes mature, they undergo physiological changes in the their outer surface, the tegument, and rapidly become refractory to vigorous immune responses. In the 1960's, researchers proposed that schistosomes evade otherwise destructive immune responses ....Schistosomes are parasitic flukes that survive in the blood vessels of their human hosts for many years. More than 200 million people are infected in developing countries, and Australian travelers to these regions are often infected. As larval schistosomes mature, they undergo physiological changes in the their outer surface, the tegument, and rapidly become refractory to vigorous immune responses. In the 1960's, researchers proposed that schistosomes evade otherwise destructive immune responses by masking their presence through the adsorption of host molecules onto the parasite surface. Intriguingly, most of the molecules adsorbed by the parasite are proteins involved in immune responses, such as MHC and immunoglobulins. In order to understand the molecular basis of schistosome maturation and masking, we recently isolated a protein that binds host IgG-Fc from the surfaces of schistosomes. We hypothesise that masking proteins expressed on the surface of developing parasites interfere with the development of protective immune responses by masking the otherwise susceptible tegument. Moreover, masking proteins are ideal candidate antigens for anti-schistosome vaccines. We now propose to test this hypothesis by identifying schistosome surface proteins that acquire host immune molecules, and isolate the genes encoding these parasite masking proteins. Masking proteins will be identified using protein-based affinity methods and differentially expressed gene- and protein-based methods. Recombinant masking proteins will then be assessed as unmasking vaccines in a mouse model of schistosomiasis. Elucidation of these aims should help to unravel the widely reported enigma of schistosome masking and the long-term survival of the parasite in the human bloodstream. By unmasking these parasites from their host-derived cloak, novel methods of controlling schistosomiasis will be revealed and efforts to develop a vaccine will be greatly accelerated.Read moreRead less