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A Dual Antigen Synthetic Peptide Subunit Vaccine Approach To Prevent Streptococcal Associated Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$604,017.00
Summary
Infection with streptococcus is responsible for causing more than 500,000 deaths each year, the majority of which are due to rheumatic fever and rheumatic heart disease, which contributes to cardiovascular disease. Our research is aimed at the development of a vaccine to prevent heart disease and involves targeting multiple molecules present on the bacterial surface. We will use a novel vaccine delivery system developed in the laboratory, which will enable the vaccine to be delivered nasally.
Determination Of Disease Specific Epitopes In Rheumatic Heart Disease In Australia
Funder
National Health and Medical Research Council
Funding Amount
$374,817.00
Summary
Rheumatic Fever and Rheumatic Heart Disease (RF-RHD) remain a significant cause of illness in Aboriginal communities in Australia. RF-RHD is a complication which follows infection with a specific bacterium. The purpose of this study is to compare the body's response and find out the patterns of antibody and immune cell reactivity to the bacterium and body proteins in RF-RHD patients and controls. It will also enable us to study the mechanisms that initiate the disease process.
Can Skin Infection With Group A Streptococcus Cause Acute Rheumatic Fever?
Funder
National Health and Medical Research Council
Funding Amount
$459,450.00
Summary
It is traditionally taught that the cause of acute rheumatic fever (ARF) is always infection of the throat with the bacterium group A streptococcus (GAS). However, in Aboriginal communities of the Top End of the Northern Territory the incidence of ARF is the highest reported in the world, yet GAS is uncommonly isolated from the throat. There is further information to suggest that GAS skin sores may underlie many cases of ARF. If this were proven, it would completely alter the traditional view of ....It is traditionally taught that the cause of acute rheumatic fever (ARF) is always infection of the throat with the bacterium group A streptococcus (GAS). However, in Aboriginal communities of the Top End of the Northern Territory the incidence of ARF is the highest reported in the world, yet GAS is uncommonly isolated from the throat. There is further information to suggest that GAS skin sores may underlie many cases of ARF. If this were proven, it would completely alter the traditional view of the cause of ARF, and have important implications for prevention of ARF around the world. Presently, these approaches focus on diagnosing and treating sore throat, but no country has proven that such a program can be successful in substantially reducing new cases of ARF. If it was known that skin infection could lead to ARF, then countries (including Australia) could emphasise the importance of skin health programs. A further benefit of this knowledge would be to influence GAS vaccine development, which presently is largely focused on the prevention of sore throat. A different possibility has recently been raised - that the cause of ARF may not always be GAS, but instead that the related bacteria GCS and GGS may have the potential to cause this disease. Proof of this hypothesis would even more dramatically alter our understanding of disease causation, prevention, and vaccine development. We propose to determine the cause of ARF in Aboriginal communities by regularly swabbing families of people with a history of ARF, and using genetic fingerprinting of the bacteria from the skin and throat swabs. When cases of ARF occur, we will be able to determine the site and type of infection that precipitated the attack. We will conduct a related study in more communities, in which we will swab family members of people with ARF and of control families (without ARF) to determine the bacteria most commonly isolated from ARF families.Read moreRead less
Antigens, Allergens And Immune Responses In Normal And Crusted Scabies
Funder
National Health and Medical Research Council
Funding Amount
$302,036.00
Summary
Scabies (itch mite), a parasitic skin infestation of the mite Sarcoptes scabiei, is a major problem among most children in many Aboriginal communities in Australia, often accompanied by streptococcal infections which cause serious diseases. Our world-first molecular studies utilised variable microsatellite markers to demonstrate that scabies mites on people are genetically distinct from those on dogs. This has important implications in control programs in Aboriginal communities. In our current N ....Scabies (itch mite), a parasitic skin infestation of the mite Sarcoptes scabiei, is a major problem among most children in many Aboriginal communities in Australia, often accompanied by streptococcal infections which cause serious diseases. Our world-first molecular studies utilised variable microsatellite markers to demonstrate that scabies mites on people are genetically distinct from those on dogs. This has important implications in control programs in Aboriginal communities. In our current NHMRC program we have cloned scabies antigens, with the aim of understanding more about immunity, which normally limits infestation from developing to the extreme levels seen in the debilitating disease crusted scabies. Our hypothesis is that crusted scabies is the consequence of an immune deficit in these patients. The first such cloned antigen is the equivalent of a known asthma-inducing allergen from a closely related housedust mite. We seek support to continue this successful program and to extend it to search for candidate vaccine antigens.The development of a vaccine would be a step of major importance in prevention. Recent reports estimate up to 300 million scabies cases worldwide, commonly associated with overcrowding and poverty. We are the first laboratory worldwide to have successfully initiated molecular studies on scabies. We have formed close collaborations with the only laboratory with an animal model (Arlian, USA), and the best group working on epidemiology and control of human scabies (Taplin, USA) and co-published with these groups. It is imperative that our NHMRC support be continued and increased to a level compatible with the importance, potential and achievements so far of this unique program.Read moreRead less
Characterisation Of Immune Responses To Sarcoptes Scabiei Cysteine Proteases, Group 1 Allergen Homologues, In Scabies
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
Scabies, a parasitic skin infestation by the 'itch' mite Sarcoptes scabiei, causes significant health problems for children and adults in many remote Aboriginal communities in Australia. Scabies is often the underlying cause of streptococcal skin infections which can cause serious complications such as kidney and heart disease. Although diagnosed scabies cases can be successfully treated, individuals have often already transmitted the disease to others prior to receiving therapy. A particularly ....Scabies, a parasitic skin infestation by the 'itch' mite Sarcoptes scabiei, causes significant health problems for children and adults in many remote Aboriginal communities in Australia. Scabies is often the underlying cause of streptococcal skin infections which can cause serious complications such as kidney and heart disease. Although diagnosed scabies cases can be successfully treated, individuals have often already transmitted the disease to others prior to receiving therapy. A particularly dreadful form of scabies, known as crusted scabies, can develop in a minority of people, in which mites multiply in their millions and the affected person develops severe crusting of the skin. This has resulted in death within 5 years for up to 50% of people with this form of scabies. Scabies mites are scientifically very similar to house dust mites, and they produce cross reactive proteins. Molecular studies in our laboratory have enabled the identification and cloning of a number of scabies molecules with considerable similarity to known house dust mite proteins that cause allergic disease. In this study we propose to focus on a group of scabies proteins with significant identity to the extensively studied Group 1 house dust mite allergens, reported to cause an immune response in 90% of mite allergic people. We propose to use these scabies mite molecules to characterise the immune response in ordinary scabies and compare it to the more severe and debilitating crusted form of the disease. Characterisation of the immune response in scabies will ultimately aid in the development of new treatment for crusted scabies based on immunotherapy. Studies will also investigate for any cross reactivity with the house dust mite group 1 molecules and enable the design of specific immunodiagnositics to distinguish house dust mite allergy from scabies infestation and thus facilitate early diagnosis of scabies carriers and better control of the infestation in endemic communities.Read moreRead less
Investigating The Molecular Basis Of Emerging Drug Resistance In Scabies Mites
Funder
National Health and Medical Research Council
Funding Amount
$516,000.00
Summary
Scabies is a disease of the skin caused by the burrowing of the 'itch' mite Sarcoptes scabiei. In remote Aboriginal communities in northern and central Australia up to 60% of children can be infected. Scabies causes intense itching of the skin, resulting in skin damage through scratching, and serious secondary bacterial infections leading to kidney and heart disease. Some remote communities in the NT are documented to have the highest rates of kidney and heart disease in the world. The location ....Scabies is a disease of the skin caused by the burrowing of the 'itch' mite Sarcoptes scabiei. In remote Aboriginal communities in northern and central Australia up to 60% of children can be infected. Scabies causes intense itching of the skin, resulting in skin damage through scratching, and serious secondary bacterial infections leading to kidney and heart disease. Some remote communities in the NT are documented to have the highest rates of kidney and heart disease in the world. The location of the Menzies School of Health Research in this region where scabies is endemic has enabled us to undertake a number of studies on the disease. Our world first molecular study using microsatellite markers demonstrated that scabies mites on people were genetically distinct from those on dogs. This had important implications in control programs in the communities. Additional work has focused on laboratory studies to monitor the sensitivity of mites to current treatments used in community control programs and for the treatment of crusted scabies, a very severe and debilitating form of the disease. We have reported evidence of increasing resistance of scabies mites to topical 5%permethrin and documented both in vitro and clinical evidence of resistance to oral ivermectin. We now seek support to extend this work to identify at the molecular level the mechanisms of resistance and use this knowledge to design a diagnostic test. This work has both local and global implications. Scabies is a significant disease of children primarily in many indigenous and third world communities, as well as associated with nursing homes and HIV infection. The tools developed in this project will enable the assessment of drug treatment failures and assist in the development of more sensitive methods for monitoring resistance in the community, including the potential for reversing it. This will avoid the current global problems of resistance observed in other organisms such as headlice.Read moreRead less
Scabies is a significant disease of children particularly in indigenous communities. This project is aimed at working out how scabies mites resist medications used to treat them and to design a test for drug resistance. The tools developed in this project will enable the assessment of treatment failures and assist in the development of more sensitive methods for monitoring resistance in the community, including the potential for reversing it.
Sympathetic Nervous System Activation In Renal Failure. Its Contribution To Pathogenesis And Progression.
Funder
National Health and Medical Research Council
Funding Amount
$490,796.00
Summary
Cardiovascular morbidity and mortality is exceedingly high in patients with chronic renal failure and particularly end stage renal disease. Recent studies suggest that sympathetic activation contributes substantially to the development of hypertension, progression of renal disease and cardiovascular prognosis in these patients. Increased sympathetic nerve firing has been demonstrated in end stage renal disease by the use of clinical microneurography, which has been attributed to uremia-related t ....Cardiovascular morbidity and mortality is exceedingly high in patients with chronic renal failure and particularly end stage renal disease. Recent studies suggest that sympathetic activation contributes substantially to the development of hypertension, progression of renal disease and cardiovascular prognosis in these patients. Increased sympathetic nerve firing has been demonstrated in end stage renal disease by the use of clinical microneurography, which has been attributed to uremia-related toxins. However, renal transplant recipients with excellent graft function and no signs of uremia still exhibit increased sympathetic nerve firing. Most interestingly, bilateral nephrectomized patients have nerve firing rates comparable to that of normal control subjects without renal disease. These data suggest that the diseased kidneys exert excitatory effects on the sympathetic nervous system independent of correction of uremia. The proposed study aims to comprehensively investigate the pattern of sympathetic activation both centrally (microneurography) and regionally (radiotracer dilution methodology) in patients with chronic renal failure and end stage renal disease . The effect of the centrally acting sympatholytic drug rilmenidine on sympathetic activity in the setting of renal disease will be assessed. Patients with ESRD waitlisted for kidney transplantation will be studied before and after transplantation. Some of the transplant recipients will also have undergone uni- or bilateral nephrectomy before transplantation which will enable us to further explore the role of the diseased kidneys in sympathetic activation. The results of this study may prove to have significant implications for treatment and prevention of cardiovascular morbid events frequently associated with renal disease.Read moreRead less
Depression And Risk Of Coronary Heart Disease: A Prospective Study Of Mediating Haemostatic Risk Factors
Funder
National Health and Medical Research Council
Funding Amount
$327,625.00
Summary
Growing evidence suggests that depression, anger and anxiety play a role in causing coronary heart disease (CHD) and complicating the outcome in existing CHD. This may occur by effects of these emotions on promoting blood clotting and the stickiness of platelets - the blood cells responsible for blood clotting. This pilot study will follow a group of people with depression but without CHD and a control group over 8 months to compare how the blood clotting profile changes as depression resolves. ....Growing evidence suggests that depression, anger and anxiety play a role in causing coronary heart disease (CHD) and complicating the outcome in existing CHD. This may occur by effects of these emotions on promoting blood clotting and the stickiness of platelets - the blood cells responsible for blood clotting. This pilot study will follow a group of people with depression but without CHD and a control group over 8 months to compare how the blood clotting profile changes as depression resolves. The potential benefits of this research are a better understanding of the links between the common illnesses of depression and CHD that might improve the prevention and treatment of heart disease.Read moreRead less
A New Model For The Pathogenesis Of Rheumatic Fever: Superantigen Priming Of The Immune Response To Group A Streptococci
Funder
National Health and Medical Research Council
Funding Amount
$248,820.00
Summary
Acute rheumatic fever (ARF) is now rare in developed countries. However, it remains a major problem in Aboriginal Australians in the NT where the rate of ARF is the highest in the world. This leads to high rates of rheumatic heart disease (up to 3% of individuals in some communities) and a premature mortality of over four times that for developing countries. Immunisation and improved living conditions offer a long-term solution but these remain a distant prospect. In the short and medium term, c ....Acute rheumatic fever (ARF) is now rare in developed countries. However, it remains a major problem in Aboriginal Australians in the NT where the rate of ARF is the highest in the world. This leads to high rates of rheumatic heart disease (up to 3% of individuals in some communities) and a premature mortality of over four times that for developing countries. Immunisation and improved living conditions offer a long-term solution but these remain a distant prospect. In the short and medium term, control of this ARF will partly depend on new and better treatment and prevention strategies. To achieve these goals a deeper understanding of the immune mechanisms underlying this disease is urgently needed. It is known that ARF is caused by an abnormal immune response following streptococcal infection. This leads to the production of cells called T cells that attack the body s own tissues rather than the bacteria itself. This autoimmune disease is responsible for the heart damage that underlies ARF. It is believed that this proces only occurs when susceptible individuals are infected with specific rheumatogenic strains of streptococci. However there are a number of deficiencies in this model and it is proposed that there is an additional factor responsible for the abnormal immune response in ARF. This project will explore the possibility that bacterial toxins called superantigens are the critical missing factor , by studying the immune response in ARF. Superantigens are produced by certain streptococci and staphylococci, and are potent in minute quantities causing widespread activation of the immune system. They have been found to play an important role in a number of autoimmune diseases and the type of immune response found in ARF fits well with that expected if superantigens were involved. If superantigens play an important role in causing the abnormal immune response in ARF then a number of new avenues would open for the treatment and prevention of this disease.Read moreRead less