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
Structure And Biosynthesis Of Entamoeba Histolytica Proteophosphoglycans
Funder
National Health and Medical Research Council
Funding Amount
$85,380.00
Summary
The intestinal parasite, Entamoeba histolytica is the cause of amoebic dysentry and liver abscess. It is the second most important parasitic disease after malaria, infecting 50 million people and causing 110 000 deaths annually. We have recently shown that the cell surface of infective stages of this parasite are coated by an unusual class of macromolecules called proteophosphoglycans (PPGs). These molecules appear to be major virulence factors, and the expression of PPGs with particular sugar m ....The intestinal parasite, Entamoeba histolytica is the cause of amoebic dysentry and liver abscess. It is the second most important parasitic disease after malaria, infecting 50 million people and causing 110 000 deaths annually. We have recently shown that the cell surface of infective stages of this parasite are coated by an unusual class of macromolecules called proteophosphoglycans (PPGs). These molecules appear to be major virulence factors, and the expression of PPGs with particular sugar modifications is associated with highly pathogenic strains. This proposal aims to determine the precise structure of the PPGs and to define functionally important domains in these molecules. We will also investigate how these molecules are assembled and processed in the parasite. In particular, we aim to characterize enzymes that generate PPG structures only found in virulent strains of Entamoeba histolytica. Assays will be established for these enzymes which will allow us to screen for inhibitors that may be used as potential anti-amoebic drugs. These studies will provide insights into the surface chemistry of these important human parasites and identify new drug targets.Read moreRead less
Host Parasite Interactions: Disease, Pathogenesis And Control
Funder
National Health and Medical Research Council
Funding Amount
$13,738,897.00
Summary
Our program will investigate two major global parasitic diseases: malaria and leishmaniasis. We will explore how the parasites identify and invade the host. This is a critical stage of the infection and we will characterise proteins involved as they are potential targets for drugs and vaccines against the parasites. Many of these recognition and interaction components are excellent candidates for the development of vaccines to interrupt the cycle of infection. We are also unravelling metabolic p ....Our program will investigate two major global parasitic diseases: malaria and leishmaniasis. We will explore how the parasites identify and invade the host. This is a critical stage of the infection and we will characterise proteins involved as they are potential targets for drugs and vaccines against the parasites. Many of these recognition and interaction components are excellent candidates for the development of vaccines to interrupt the cycle of infection. We are also unravelling metabolic pathways unique to the parasites using a mixture of genetic and computational tools complemented with sophisticated instrumentation to chemically identify the parasite�s entire repertoire of metabolic compounds. These pathways, absent from human hosts, are also highly vulnerable and we will feed the key steps into the drug development facet of the program. Our program also looks at how the parasites cause disease and how the host responds to the disease. We will explore the reactions of the immune system to infection and consequences of the body�s (often only partially successful) attempts to fight off the disease.Read moreRead less
Mechanisms Of In Vivo Modulation Of Granulomatous Inflammation In Human Schistosomiasis
Funder
National Health and Medical Research Council
Funding Amount
$276,598.00
Summary
Schistosomiasis is a serious parasitic disease responsible for up to 300,000 deaths annually. The cause are blood flukes that produce considerable disease severity, resulting from host inflammation against the parasite eggs lodging in the liver, giving rise to fibrosis, liver damage, enlarged spleen and death. The pathogenesis is regulated by molecules called cytokines and this project will unravel the mechanisms that regulate disease progression to the severe forms of chronic schistosomiasis.
Function And Inhibition Of Plasmepsin V In Targeting Malaria Virulence Proteins Into Human Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$407,845.00
Summary
Malaria parasites dramatically renovate infected erythrocytes to survive and evade the host immune system by delivering hundreds of exported parasite proteins into the cell. The parasite protease Plasmepsin V is essential for protein export. We aim to develop potent inhibitors of this protease in the hope of blocking its function and killing the parasite. We also aim to discover the components of the trafficking pathway after cleavage by Plasmepsin V that sorts virulence proteins to the host cel ....Malaria parasites dramatically renovate infected erythrocytes to survive and evade the host immune system by delivering hundreds of exported parasite proteins into the cell. The parasite protease Plasmepsin V is essential for protein export. We aim to develop potent inhibitors of this protease in the hope of blocking its function and killing the parasite. We also aim to discover the components of the trafficking pathway after cleavage by Plasmepsin V that sorts virulence proteins to the host cell.Read moreRead less
Identification And Development Of Novel Vaccine Candidates For Malaria
Funder
National Health and Medical Research Council
Funding Amount
$4,000,000.00
Summary
The aim is to improve methods of preventing and treating malaria by understanding the basic biological mechanisms the pathogen that causes the most severe form of human malaria, uses to invade and survive in the host erythrocyte, and survives in the hostile environment of the blood, as this determines disease outcome. I have outlined an ambitious program for the next five years that will utilize our basic knowledge of how this parasite infects and causes disease to identify novel vaccine candida ....The aim is to improve methods of preventing and treating malaria by understanding the basic biological mechanisms the pathogen that causes the most severe form of human malaria, uses to invade and survive in the host erythrocyte, and survives in the hostile environment of the blood, as this determines disease outcome. I have outlined an ambitious program for the next five years that will utilize our basic knowledge of how this parasite infects and causes disease to identify novel vaccine candidates from the genome of P. falciparum. This represents a major task that will not only provide new information for the malaria field but also identify the most promising candidates that will be pursued into clinical development. I will use two strategies; firstly, a consortium will be formed that brings together expertise that will credential the P. falciparum genome. This provides our experience in functional genomics with EHIME University who have developed methods to express correctly folded P. falciparum proteins in a high throughput system using wheat germ in vitro translation and University of Pennsylvania who have expertise in bioinformatics of the malaria genome. It provides the critical mass and expertise required for a major project. We have developed novel methods for expression of protein domains on the surface of the P. falciparum-infected erythrocyte and this has important utility for analysis of function and immune responses to these proteins. To utilize and develop these tools I will build a critical mass of expertise by forming a consortium between Australian scientists together with Papua New Guinea Institute of Medical Research, KEMRI Institute for Geographic Medicine (Kenya), Harvard University and the Swiss Tropical Institute (Switzerland). This consortium will provide access to malaria endemic areas and the expertise in fieldwork and epidemiology to fully utilize the parasite lines we will construct. The formation of these consortia will greatly strengthen our ability to identify the most promising candidates for clinical development. This will also have great benefit to Australia by increasing the internationalization of our science and therefore access of our researchers to other expertise and also provides a means for networking outside of this country. To foster and increase our leadership in malaria I will develop a Functional Genomics facility that will provide the capacity to construct large panels of transgenic parasites and the ability to develop new genetic tools. Additionally, I will develop a specialized microscopy facility at WEHI to provide the advanced equipment required for visualizing molecular events in live cells. This facility will include a number of instruments including a Line scanner confocal that will be essential for following cellular events such as protein trafficking in live parasite lines.Read moreRead less
Immunomodulatory Molecules Of Parasitic Helminths As Novel Therapeutics For Allergic Disorders.
Funder
National Health and Medical Research Council
Funding Amount
$321,532.00
Summary
Australia has one of the highest rates of asthma in the world with almost 3 million Australians are affected by this disease. Previous research has shown that infection with various types of parasitic worms lessens the severity of asthma. The aim of this research is to find out why this happens and to isolate the ingredients from the parasite that suppress asthma. Once found, these molecules can be used to create new drugs for the prevention of asthma and allergies in children and adults.