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Transport Pathways Of Host-derived Iron In Schistosomes Parasites
Funder
National Health and Medical Research Council
Funding Amount
$322,091.00
Summary
This project will identify the diversity and biological roles of receptors for metabolic iron expressed on the body surface of the parasitic blood flukes (schistosomes) of humans. Schistosomes are a major health problem in many tropical countries and are responsible for significant human morbidity and lost productivity. Adult worms feed on human blood, from which derive amino acids for the production of many hundreds of eggs released per day into the human blood stream. The intense cellular resp ....This project will identify the diversity and biological roles of receptors for metabolic iron expressed on the body surface of the parasitic blood flukes (schistosomes) of humans. Schistosomes are a major health problem in many tropical countries and are responsible for significant human morbidity and lost productivity. Adult worms feed on human blood, from which derive amino acids for the production of many hundreds of eggs released per day into the human blood stream. The intense cellular response induced by parasite eggs trapped in body organs is the major cause of chronic human disease. We have discovered two intriguing phenomena of iron metabolism in schistosomes. Firstly, schistosomes have a greater reliance on iron than many other organisms, storing a surfeit in cells that produce the protein-rich egg shell. Secondly, a major transmembrane iron transporter of the parasites, thought to be involved in the uptake of iron, is found on the parasite external body surface and not in the parasite intestine. The extensive nutritional dependence of these worms on iron and the surface location of mediators of iron uptake raise the exciting possibility that we have uncovered a novel system that might be exploited for vaccine or drug-mediated control of these significant human parasites. If we can dissect the pathways schistosomes use to derive iron from their hosts, we may be able to generate vaccines to block this nutritional pathway, or use drugs to block embryogenesis. This project is a fact-finding mission that asks if the host-interactive tegument of these parasites is a major source of metabolic iron. Molecules we demonstrate to be present on the surface will be tested as vaccine candidates in mouse vaccine trialsRead moreRead less
Polysaccharide Biosynthesis As A New Drug Target In Leishmania Parasites
Funder
National Health and Medical Research Council
Funding Amount
$422,517.00
Summary
Leishmania are protozoan parasites that cause a number of important diseases in humans, afflicting more than 12 million people worldwide. There are currently few drugs that target infectious disease causing stages of these parasites. We have recently shown that Leishmania parasites accumulate a highly unusual sugar polymer when they infect mammalian cells, which appears to be important for infectivity. In this proposal , we will investigate how this sugar polymer is made, identify enzymes involv ....Leishmania are protozoan parasites that cause a number of important diseases in humans, afflicting more than 12 million people worldwide. There are currently few drugs that target infectious disease causing stages of these parasites. We have recently shown that Leishmania parasites accumulate a highly unusual sugar polymer when they infect mammalian cells, which appears to be important for infectivity. In this proposal , we will investigate how this sugar polymer is made, identify enzymes involved in its synthesis and develop new chemical tools for generating highly specific inhibitors of Leishmania sugar biosynthesis. This project will provide new insights into processes that are essential for the survival and infectivity of an improtant group of human pathogens, and lead to the development of new classes of enzyme inhibitors with anti-parasite activity.Read moreRead less
Tissue Specific Antigen Presenting Cell Functions During Infection.
Funder
National Health and Medical Research Council
Funding Amount
$555,325.00
Summary
T cell activation is often inefficient following infection or vaccination, resulting in poor control of pathogens. In this grant, we propose to investigate the cellular basis for sub-optimal CD4+ T cell activation following infection. Specifically, we will study the roles of antigen presenting cells in CD4+ T cell activation in an experimental model of visceral leishmaniasis caused by the human protozoan parasite Leishmania donovani.
Metabolomic Analysis Of Leishmania Parasites; Identifying Metabolic Pathways Required For Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$605,963.00
Summary
Leishmania are single-celled parasites that target a major class of immune cell, affecting millions and killing thousands of people worldwide. We have developed new approaches for investigating how these parasites survive in the immune cells, and why different species of Leishmania cause markedly different pathologies. This information will be used to identify and validate new drug targets in these parasites.
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.
Immunological Prevention Of Cysticercosis And Hydatid Disease
Funder
National Health and Medical Research Council
Funding Amount
$510,000.00
Summary
Cysticercosis and hydatid disease are caused by infections with the larval stages of tapeworm parasites. These infections cause substantial morbidity and mortality throughout the world, but particularly in developing countries. They are zoonotic diseases, being transmitted to humans from animals. This project aims to develop practical vaccines to assist with the prevention of both cysticercosis and hydatid disease in humans. The vaccines will be used in the parasites' natural animal hosts, there ....Cysticercosis and hydatid disease are caused by infections with the larval stages of tapeworm parasites. These infections cause substantial morbidity and mortality throughout the world, but particularly in developing countries. They are zoonotic diseases, being transmitted to humans from animals. This project aims to develop practical vaccines to assist with the prevention of both cysticercosis and hydatid disease in humans. The vaccines will be used in the parasites' natural animal hosts, thereby breaking the parasite life-cycle and preventing the diseases being passed to humans. Substantial preliminary research has been undertaken by the applicant, including completion of successful preliminary vaccine trials. This project will optimise the vaccines and complete initial field trials in countries with high rates of disease transmission.Read moreRead less
From Maps To Efficient Multi-parasite Control In The Philippines
Funder
National Health and Medical Research Council
Funding Amount
$358,121.00
Summary
Schistosomiasis and soil-transmitted helminths are major parasitic infections in Asia, causing anaemia, poor growth and poor school performance and death in some chronic schistosomiasis cases. We will use maps to demonstrate the geographic distribution of these parasites in the Philippines. We will estimate the impact and costs and benefits of parasite control programmes. This research will help plan more efficient parasite control and reduce the impact of these infections in the Philippines.
Impact Of The Three Gorges Dam On Transmission And Future Control Of Human Schistosomiasis In China
Funder
National Health and Medical Research Council
Funding Amount
$1,420,135.00
Summary
A million Chinese have schistosomiasis or snail fever. When the Three Gorges Dam on the Yangtze River is fully operational, considerable environmental-ecological changes will result, increasing spread of this parasitic disease. In a unique study we will assess the impact of the Dam on schistosomiasis, and test and model a series of options for its control. The findings will be important for China and other areas where schistosomiasis occurs and where similar dams are planned or are under way.
Development Of Purine Nucleoside Phosphonates As Anti-malarial Drugs Targeting Nuceloside Synthesis In Plasmodium
Funder
National Health and Medical Research Council
Funding Amount
$428,917.00
Summary
Malaria is one of the most serious infectious diseases today. Because of its location in a malaria endemic region, the tropical regions (above 19 S in latitude) of Australia face an emerging threat. The causative agent of the disease is the parasite, Plasmodium. Because of increasing resistance to existing medicines, new drugs are now needed. The drugs we will develop target the parasites replication cycle and are related in structure to those in use to treat viral infections including AIDS.
Defining The Roles Of TNF, Lymphotoxin Alpha And LIGHT In Experimental Visceral Leishmaniasis
Funder
National Health and Medical Research Council
Funding Amount
$410,148.00
Summary
Visceral leishmaniasis (VL) is an important human disease caused by the protozoan parasites Leishmania donovani and L. infantum (chagasi). Studies in experimental VL caused by L. donovani infection of mice have resulted in major insights into the causes of VL and the reasons why VL patients become severely immunocompromised. Work from our laboratory has shown that members of the TNF family of cytokines play key roles in the generation of effective immune responses during VL, but also mediate sig ....Visceral leishmaniasis (VL) is an important human disease caused by the protozoan parasites Leishmania donovani and L. infantum (chagasi). Studies in experimental VL caused by L. donovani infection of mice have resulted in major insights into the causes of VL and the reasons why VL patients become severely immunocompromised. Work from our laboratory has shown that members of the TNF family of cytokines play key roles in the generation of effective immune responses during VL, but also mediate significant tissue pathology, particularly in the spleen, following L. donovani infection. In this grant, we will define the roles of several key members of the TNF family in the generation of immunity and pathology during experimental VL. We will also test if the activity of these molecules can be modulated to control disease without detrimental side effects. Results from this research have implication for the design of new vaccines and therapeutics to control VL. In addition, given the important role of TNF family members in cancers and autoimmune diseases, the work in this grant will have advance our understanding of pathogenic processes that are common to many important human diseases.Read moreRead less