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.
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.
Assessment Of Transgenic Plants Expressing Malaria Antigens As A Means Of Inducing Protective Immunity
Funder
National Health and Medical Research Council
Funding Amount
$112,000.00
Summary
Malaria infection of humans is one of the most important and deadly infectious diseases in the world, killing more than two million people each year. Traditionally, drugs and insecticides have been used to treat the disease and control its spread. Unfortunately, both of these have become much less effective and there now exist untreatable cases of malaria. Alternative control measures are urgently needed and this project focusses on the development of such an alternative, a vaccine against malar ....Malaria infection of humans is one of the most important and deadly infectious diseases in the world, killing more than two million people each year. Traditionally, drugs and insecticides have been used to treat the disease and control its spread. Unfortunately, both of these have become much less effective and there now exist untreatable cases of malaria. Alternative control measures are urgently needed and this project focusses on the development of such an alternative, a vaccine against malaria using plants transgenic for genes encoding vaccine molecules. Growing these plants not only provides a potentially inexpensive vaccine production system but also offers a potential delivery system such that immunisation may be possible simply through consumption of an edible vaccine. This project intends to investigate the possibility of using transgenic plants expressing malaria antigens to induce protective immunity against malaria infection. The results of this project will provide vitally important information in malaria vaccine production and delivery.Read moreRead less
Transduction Of Schistosoma Mansoni Using Boudicca, An Endogenous Retrotransposon Of Schistosomes
Funder
National Health and Medical Research Council
Funding Amount
$445,328.00
Summary
Blood flukes that cause schistosomiasis are endemic in 76 countries; it is estimated that as many as 300 million people are infected, and that another 600 million live at risk of infection. The parasitic worms deposit eggs into the blood vessels of the human gut and liver causing chronic inflammation. The disease kills only a small proportion of patients however the long-term pain and suffering creates a huge economic burden on developing countries that surpasses that of most other endemic disea ....Blood flukes that cause schistosomiasis are endemic in 76 countries; it is estimated that as many as 300 million people are infected, and that another 600 million live at risk of infection. The parasitic worms deposit eggs into the blood vessels of the human gut and liver causing chronic inflammation. The disease kills only a small proportion of patients however the long-term pain and suffering creates a huge economic burden on developing countries that surpasses that of most other endemic diseases. Control largely relies on the drug praziquantel however its wide scale use has led to concerns that drug resistance will develop. New Drugs or control strategies will soon be required. In 1994 the World Health Organisation Schistosome Genome Project was initiated aiming at identifying target genes that will enable scientists to develop new drugs and vaccines. It is anticipated the complete genome of the worm will be reported within the next 12 months and methods are desperately needed to determine the importance of each gene in the pathways that may make good candidates for drugs and vaccines aimed at killing the parasite. In this study we will use an endogenous retrotransposon that we have identified in the parasite as a vehicle to genetically manipulate the worm. This will help to understand the function and importance of novel antigens that have been discovered by the genome project. To test this method we will use RNA interference (RNAi) to analyse gene function. This technology employs a naturally occurring pathway that uses short RNA molecules to very specifically control the formation of gene products. We propose to construct virus-like elements to deliver these RNAs. The flukes feed on blood and we will inhibit key digestive enzymes to determine if they might make effective targets for drugs and vaccines. In terms of public health, this investigation seeks to establish novel methods to aid the development of new therapies to treat and control schistosomiasis.Read moreRead less
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.
Targeting The Mannose Activation Pathway In Leishmania - Novel Drug Targets And Vaccines.
Funder
National Health and Medical Research Council
Funding Amount
$338,661.00
Summary
Leishmaniasis is a parasitic disease ranging in severity from skin lesions to fatal systemic infection. It is a serious public health problem throughout many regions of the world. Co-infection with HIV has emerged as a serious problem in Africa, South America and southern Europe. Recently, leishmaniasis has been identified in East Timor and in kangaroos in Australia. Treatment of leishmaniasis is based on chemotherapy, but currently used drugs are expensive, have high toxicity and unwanted side ....Leishmaniasis is a parasitic disease ranging in severity from skin lesions to fatal systemic infection. It is a serious public health problem throughout many regions of the world. Co-infection with HIV has emerged as a serious problem in Africa, South America and southern Europe. Recently, leishmaniasis has been identified in East Timor and in kangaroos in Australia. Treatment of leishmaniasis is based on chemotherapy, but currently used drugs are expensive, have high toxicity and unwanted side effects. They have also been compromised by the emergence of resistance in the parasite. Leishmania synthesises a range of surface molecules, which are needed for virulence and parasite survival in the host. The biosynthesis process of these molecules requires activated mannose. We have identified two novel parasite genes encoding for enzymes, which are essential for the biosynthesis of surface virulence factors. When either of these genes is deleted the parasite can no longer cause disease. This suggests that drugs targeting the two enzymes will be able to control the infection. We will produce crystals of these enzymes and solve their 3D structure using state of the art technology to screen libraries of synthetic chemicals to find candidate inhibitors of enzyme activity. When these compounds are identified we will use computer modelling to design compounds based on these inhibitors and crystal structure, which will lead to a new generation of anti-Leishmania drugs. We will also determine whether the avirulent parasites can be used as an attenuated vaccine. Recovery from infection leads to a solid immunity and protection from subsequent infection indicating that vaccination is feasible, but despite of a huge amount of research there is no antileishmanial vaccine currently available. This study will lead to potential novel antileishmanial drugs and vaccines. It will also provide fundametal new knowledge of the structure of enzymes critical for parasite virulence.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
Functional Studies On Two Essential Rhoptry Proteins Of The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$470,894.00
Summary
Malaria is one of the most important and deadly infectious diseases in the world, causing 250 million cases and nearly one million deaths each year. Traditionally, drugs and insecticides have been used to treat the disease and control its spread. They have become much less effective and there now exist untreatable cases of malaria. Alternative control measures are urgently needed. An understanding of how proteins essential to parasite survival operate may identify novel targets for therapeutic i ....Malaria is one of the most important and deadly infectious diseases in the world, causing 250 million cases and nearly one million deaths each year. Traditionally, drugs and insecticides have been used to treat the disease and control its spread. They have become much less effective and there now exist untreatable cases of malaria. Alternative control measures are urgently needed. An understanding of how proteins essential to parasite survival operate may identify novel targets for therapeutic intervention against this devastating disease.Read moreRead less
Dissecting The Contribution Of Malaria Translocon Components To Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$326,583.00
Summary
The malaria parasite exports hundreds of proteins into its host red blood cell via a unique protein export machinery. This enables the parasite to avoid immune detection, resulting in over one million deaths annually. This proposal will use a rodent malaria infection model to address the functional significance and contribution of the machinery to malaria disease to discern if it will provide a potential target for anti-malaria drugs.
Towards Novel Therapies For Scabies: Functional Analysis Of Sarcoptes Scabiei Aspartic Proteases.
Funder
National Health and Medical Research Council
Funding Amount
$328,231.00
Summary
Scabies is a significant problem in disadvantaged populations worldwide, particularly Australian Aboriginal communities where up to 65% of people can be affected. Our research will investigate the role that aspartic proteases play in the interaction of the mite with its host. We will examine methods of interfering with the function of these proteins with the aim of designing new, effective treatments for scabies.