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.
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.
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
Shigella Flexneri O Antigen Polysaccharides: Biosynthesis, Function In Virulence, And Interaction With IcsA/VirG
Funder
National Health and Medical Research Council
Funding Amount
$468,055.00
Summary
Shigella flexneri bacteria cause dysentery in millions of humans each year. The bacterium invades and replicates within the cells of the large intestine. Inside cells, S. flexneri is able to use the host cell's actin-based motility machinery to become motile within the cells, and this can be seen as F-actin comet tails extending from one end of the cell. Bacterial cell surface components residing in the outer membrane are important for the bacterium's ability to cause disease. Two of these compo ....Shigella flexneri bacteria cause dysentery in millions of humans each year. The bacterium invades and replicates within the cells of the large intestine. Inside cells, S. flexneri is able to use the host cell's actin-based motility machinery to become motile within the cells, and this can be seen as F-actin comet tails extending from one end of the cell. Bacterial cell surface components residing in the outer membrane are important for the bacterium's ability to cause disease. Two of these components (lipopolysaccharides (LPS) and their polysaccharide chains (O antigens), and IcsA-VirG protein)) are required for initiating actin polymerisation, and mutations affecting synthesis of these components reduce ability to cause disease. In previous studies we have found that O antigen and the synthesis and function of IcsA are interrelated. This project will study how the O antigens are synthesised and their chain length determined by the Wzz protein, and the Wzz structure in relation to its function will also be characterised. The role played by O antigen in intracellular motility will be studied to determine the mechanisms involved. Infection of cells and cell free extracts, antibodies, and an enzyme which specifically degrades the O antigen, will be used to study how O antigen affect the interaction between bacteria with human cell proteins. The relationship between O antigen and IcsA function will be studied using monoclonal antibodies raised to IcsA. The effect of LPS on the outer membrane protease IcsP will be investigated, as will the effect of LPS lipid A mutations on O antigen and virulence. These studies will contribute to a better understanding of the biosynthesis of an ubiquitous bacterial cell surface component (O antigen), its function as a virulence factor in bacterial interactions with host cells. This may lead to novel therapeutic strategies to prevent and control Shigellosis and other bacterial infections.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE160101281
Funder
Australian Research Council
Funding Amount
$300,036.00
Summary
Biomimetic lipidic self-assembly materials for protein encapsulation. This project intends to improve understanding of the interactions between proteins and lipidic materials to guide the development of new biomaterials. Proteins and peptides play an increasingly important role as drugs, vaccines and diagnostics. However, these fragile, often large, macromolecules come with challenges for drug delivery. Lipid-based materials are ideal matrices for encapsulation of functionally active proteins. T ....Biomimetic lipidic self-assembly materials for protein encapsulation. This project intends to improve understanding of the interactions between proteins and lipidic materials to guide the development of new biomaterials. Proteins and peptides play an increasingly important role as drugs, vaccines and diagnostics. However, these fragile, often large, macromolecules come with challenges for drug delivery. Lipid-based materials are ideal matrices for encapsulation of functionally active proteins. They also offer advantages as drug delivery vehicles including controlled release properties. The combination of strategies creates an ideal delivery system for protein therapeutics. The project aims to characterise the physicochemical interactions between the protein and the lipid matrix. This may guide the development of novel lipidic materials for the encapsulation and controlled release of protein therapeutics.Read moreRead less