Structural Diversity And Evolution Of Variant-specific Surface Proteins In The Protozoan Parasite, Giardia
Funder
National Health and Medical Research Council
Funding Amount
$436,417.00
Summary
Giardia are well-known as a cause of travellers' diarrhoea, but our knowledge about these parasites remains rudimentary. Infections are common in Australia, especially in day-care centres and outback Aboriginal communities. The 1998 Sydney water crisis highlighted the necessity of monitoring reservoirs and reticulated water for contamination by faecal cysts of both human and animal origin. The aim of this project is to learn more about the 'coat' proteins which cover the organisms. These protect ....Giardia are well-known as a cause of travellers' diarrhoea, but our knowledge about these parasites remains rudimentary. Infections are common in Australia, especially in day-care centres and outback Aboriginal communities. The 1998 Sydney water crisis highlighted the necessity of monitoring reservoirs and reticulated water for contamination by faecal cysts of both human and animal origin. The aim of this project is to learn more about the 'coat' proteins which cover the organisms. These protect the parasites against digestion, enabling them to reside indefinitely within the intestine. However, the proteins are also the principal target of host immunity. Analysis of Giardia populations has shown that as many as 150-200 different coat proteins can be made. Although individual cells have coats comprised of only a single protein type, these can 'switch' spontaneously to production of another type - a phenomenon known as 'antigenic variation'. This process occurs slowly but continuously, giving rise to 'variants' which survive successive host responses (directed against each predominant coat type) and occupy the vacancies left by the destruction of their immediate forebears. It is important to gain information about the structural diversity of these variant-specific proteins (VSP), as any 'Giardia' vaccine is likely to require inclusion of each major type. It is also important to elucidate how the 'switching' process occurs, as this may provide clues as to how it might be interrupted. The project addresses both aspects.Read moreRead less
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
Var Gene Diversity And Naturally Acquired Immunity To Malaria
Funder
National Health and Medical Research Council
Funding Amount
$410,664.00
Summary
In areas where malaria is common, people develop natural immunity to the disease albeit very slowly due to the many parasite strains that circulate. The project will use protein microarrays to investigate the patterns by which antibodies are acquired to the majority of strains. This will reveal how antibodies are acquired with age and which are associated with protection against malaria symptoms. The research aims to identify biomarkers of malaria immunity and may lead to new vaccine candidates.
Immunological Prevention Of Hydatid Disease And Cysticercosis
Funder
National Health and Medical Research Council
Funding Amount
$345,340.00
Summary
This project seeks to develop practical vaccines to control the transmission of cysticercosis and hydatid disease. These diseases are caused by infection with the larval stages of tapeworm parasites which have a worldwide distribution and cause substantial human morbidity and mortality. The parasites are transmitted to humans from animals. Methods for control of transmission of infection currently rely on public education and anthelmintic treatment of animals. These measures are often ineffectiv ....This project seeks to develop practical vaccines to control the transmission of cysticercosis and hydatid disease. These diseases are caused by infection with the larval stages of tapeworm parasites which have a worldwide distribution and cause substantial human morbidity and mortality. The parasites are transmitted to humans from animals. Methods for control of transmission of infection currently rely on public education and anthelmintic treatment of animals. These measures are often ineffective and there is an urgent need for new tools to help control transmission of these important diseases. Previous research has shown that the animal hosts of these parasites can be protected from infection by vaccination. Prevention of infection in the parasites' animal hosts has the effect of breaking the parasite life cycle and indirectly removes the source of infection for humans. This project will further develop an existing vaccine against hydatid disease, will develop a new vaccine against cysticercosis and will participate in initial international parasite control campaigns based on application of these vaccines.Read moreRead less
Understanding The Pharmacoregulation Of The Extracellular Calcium Sensing Receptor.
Funder
National Health and Medical Research Council
Funding Amount
$744,943.00
Summary
Calcium sensing receptors (CaSR) are important regulators of hormone release and modulators of kidney transport, digestion-absorption-satiety and bone mass. In each case, CaSRs adopt a characteristically distinct activating mechanism that we will unravel in detail sufficient for the development of novel chemotherapies e.g., for osteoporosis and obesity. We also anticipate early application of CaSR-based therapies to clinically significant genetic disorders e.g., neonatal hyperparathyroidism.
Population Genomics Of Plasmodium Falciparum Surface Antigen Genes
Funder
National Health and Medical Research Council
Funding Amount
$385,319.00
Summary
Like most other organisms, each malaria parasite has unique characteristics. A malaria vaccine will need to incorporate these differences to be effective against all parasites in a population. This project will measure the variability and fluctuations of eight of the most promising vaccine targets in a number of natural malaria populations. With this knowledge, a vaccine that is effective against all parasites in the population can be developed and its future success maintained.