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
Genome-based Tools To Support Urogenital Schistosomiasis Control
Funder
National Health and Medical Research Council
Funding Amount
$429,644.00
Summary
More than 100 million sub-Saharan Africans have urogenital schistosomiasis, a disease that promotes malignant cancer and HIV/AIDS. Control depends on a single drug, making resistance an imminent threat. We will deliver new molecular tools to assess parasite genetic diversity and to prioritise a panel of anti-parasitic drug targets and vaccine candidates. These outcomes will deliver the next generation of interventions against urogenital 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.
Optimising Large-scale Public Health Interventions To Control Neglected Tropical Diseases
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Neglected tropical diseases (NTD) are a group of health conditions that affect the poorest of the poor, particularly in remote and rural areas. They affect the most vulnerable communities and cause substantial, chronic health harms impairing personal and social development. Several debilitating NTD are common in remote indigenous communities and Pacific islands. I propose a series of studies to investigate new strategies to control NTD in large populations where these diseases are endemic.
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
Functional Dissection Of Invasion Motor Regulation In Toxoplasma Gondii
Funder
National Health and Medical Research Council
Funding Amount
$500,396.00
Summary
The single-celled intracellular parasite Toxoplasma gondii is the cause of Toxoplasmosis and can be the basis of illness in immunocompromised individuals, eye disease and congenital birth defects. After host cell recognition Toxoplasma needs to activate the invasion machinery to establish a successful infection. We will reveal, at the molecular level, how Toxoplasma achieves this and then screen for drugs that inhibit this process. Compounds identified in this project could act as lead compounds ....The single-celled intracellular parasite Toxoplasma gondii is the cause of Toxoplasmosis and can be the basis of illness in immunocompromised individuals, eye disease and congenital birth defects. After host cell recognition Toxoplasma needs to activate the invasion machinery to establish a successful infection. We will reveal, at the molecular level, how Toxoplasma achieves this and then screen for drugs that inhibit this process. Compounds identified in this project could act as lead compounds to develop new treatments for Toxoplasmosis.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.
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
Does Mass Drug Administration For Scabies Result In Control Of Serious Bacterial Complications? A Proof Of Concept Towards Global Elimination.
Funder
National Health and Medical Research Council
Funding Amount
$883,760.00
Summary
Scabies is common skin disease in developing countries, in particular in the Pacific region. In Fiji, one in two children suffer from the infestation, which affects over 20% of the population. A recent study conducted in Fiji on 2000 people showed that mass drug administration (MDA) with oral ivermectin is a safe and effective way to reduce the burden of scabies in the community. We will expand the MDA program to 100,000 people, the largest study of MDA ivermectin for scabies ever undertaken.