Investigating The Role For Microparticles In The Pathogenesis Of Cerebral Malaria.
Funder
National Health and Medical Research Council
Funding Amount
$293,931.00
Summary
Fatal malaria is one of the world's most destructive disease burdens. A major complication is Cerebral Malaria (CM). Small vesicles originating from cell membranes, known as microparticles (MP), have recently been shown to play an important role in CM. This project aims to determine the role MP play in CM, the cells they interact with and the consequences of such interactions. It is hoped that project outcomes may provide new approaches in the prevention and treatment of fatal malaria.
Screening Agents Active Against The Late-stage Inflammatory Cytokines For Activity Against Influenza Disease
Funder
National Health and Medical Research Council
Funding Amount
$241,409.00
Summary
Infection with a virulent influenza virus that the body has never encountered before, particularly H5N1, sends the immune system into overdrive, and causes a massive release of proteins (inflammatory cytokines), known as a cytokine storm, that in and of itself leads to death. The object of this research is to screen, in a mouse influenza model, agents known to prevent this occurring and antagonise it once it has occurred. This will be done with and without Tamiflu, a standard anti-influenza drug ....Infection with a virulent influenza virus that the body has never encountered before, particularly H5N1, sends the immune system into overdrive, and causes a massive release of proteins (inflammatory cytokines), known as a cytokine storm, that in and of itself leads to death. The object of this research is to screen, in a mouse influenza model, agents known to prevent this occurring and antagonise it once it has occurred. This will be done with and without Tamiflu, a standard anti-influenza drug.Read moreRead less
Microbiological And Immunological Determinants Of Prolonged Illness Following Q Fever.
Funder
National Health and Medical Research Council
Funding Amount
$362,036.00
Summary
Q fever is a severe, sometimes life-threatening infection acquired by individuals who work with livestock, particularly abattoir workers. At least 10% of individuals who develop Q fever experience prolonged ill-health in the form of weeks or months of debilitating fatigue, profuse night sweats, headaches, as well as muscle and joint pains. This poorly understood persistent illness is associated with substantial disability and loss of income. This research is based upon an established cohort stud ....Q fever is a severe, sometimes life-threatening infection acquired by individuals who work with livestock, particularly abattoir workers. At least 10% of individuals who develop Q fever experience prolonged ill-health in the form of weeks or months of debilitating fatigue, profuse night sweats, headaches, as well as muscle and joint pains. This poorly understood persistent illness is associated with substantial disability and loss of income. This research is based upon an established cohort study in which subjects with acute, documented Q fever are recruited shortly after the onset of symptoms and followed at regular intervals through to recovery or persistent symptoms. The aim of this research is to determine whether abnormal persistence of the causative organsim of Q fever, Coxiella burnetii, underlies the continued symptoms in those who do not recover promptly from the acute illness. Furthermore, the research is examining the host defense response against the organism via the production of cytokines or immunological hormones, to determine whether these proteins mediate the ongoing symptoms. If confirmed, these hypotheses would lead the way to diagnostic markers for the disorder and a rational treatment strategy.Read moreRead less
Genetic Modulation Of The Host Response To Pulmonary TB
Funder
National Health and Medical Research Council
Funding Amount
$540,273.00
Summary
Tuberculosis (TB) is an enormous global health problem. The World Health Organisation estimates that TB, which is caused by infection with the bacteria Mycobacterium tuberculosis, infects 2 billion individuals, leading to 2 million deaths and 8 million new cases of disease per year. Most TB disease is not manifest at the time of infection, but is a reactivation of latent disease in people who do not completely eradicate the primary infection. In a latent infection an effective chronic host respo ....Tuberculosis (TB) is an enormous global health problem. The World Health Organisation estimates that TB, which is caused by infection with the bacteria Mycobacterium tuberculosis, infects 2 billion individuals, leading to 2 million deaths and 8 million new cases of disease per year. Most TB disease is not manifest at the time of infection, but is a reactivation of latent disease in people who do not completely eradicate the primary infection. In a latent infection an effective chronic host response contains dormant TB organisms inside activated macrophages. Cells are recruited to wall off infected macrophages and specific T cells continually induce the activate state with minimal tissue damage (immunopathology). Although currently available antibiotics can kill TB organisms, the treatment is prolonged, expensive, difficult to administer in poorly resourced regions and not effective against multi-drug resistant organisms. New therapies to treat both active disease and prevent reactivation in individuals who are latently infected are urgently required. This proposal will address this problem using a novel approach, namely gene manipulation to augment host immunity to TB and limit concurrent immunopathology. We will construct vectors to increase expression of the key immune molecules, the T lymphocyte activating cytokines IL-12 and IL-23, and the macrophage effector molecules LRG-47 and Indoleamine 2,3-Dioxygenase (IDO). These molecules are known to be involved in TB killing. We will determine if increasing their expression increases the killing capacity of TB-infected macrophages and we will examine how these molecules interact to aid clearance of the TB bacilli. This internationally competitive grant will further our detailed understanding of the complex immune response to TB organisms and lead to the development of novel therapies to treat TB infection and prevent reactivation of latent disease.Read moreRead less
Enhancement Of Mucosal Immunity And CTL Avidity Against HIV-1
Funder
National Health and Medical Research Council
Funding Amount
$553,070.00
Summary
Production of strong antiviral immunity at the local mucosa (genito-rectal track) is essential for protection against HIV-AIDS. We believe that expression of small hormone-like molecules known as Th2 cytokines IL-4-IL-13 negatively influence the generation of protective immunity against HIV. Thus we aim to counteract these effects by co-expressing proteins known as chemokines together with vaccine antigens to improve the quality of mucosal vaccine immunity.
We plan to continue our work that to date is consistent with the idea that excessive induction of the enzyme iNOS, and thus production of nitric oxide in key locations, is a central event in how falciparum malaria kills people who become infected with this parasite. This will largely be based on detecting iNOS and nitrotyrosine in tissues from autopsies collected as part of a malaria research programme conducted in Malawi. Laboratory experiments will also be performed. In particular, there is a ....We plan to continue our work that to date is consistent with the idea that excessive induction of the enzyme iNOS, and thus production of nitric oxide in key locations, is a central event in how falciparum malaria kills people who become infected with this parasite. This will largely be based on detecting iNOS and nitrotyrosine in tissues from autopsies collected as part of a malaria research programme conducted in Malawi. Laboratory experiments will also be performed. In particular, there is a body of evidence that suggests the following interactions between inflammatory cytokines and salicylate, with important practical ramifications, in children. 1. Salicylate toxicity, like the acute multi-organ form of childhood malaria it mimics, is probably caused by excess systemic iNOS induction. This plausibly includes the metabolic acidosis, hypoglycaemia, seizures, coma and cerebral oedema seen in both conditions. Both are thus logically susceptible to treatment with specific iNOS inhibitors. 2. The same picture would arise in children when smaller doses of salicylate synergise with IFN-g, IL-1b, and perhaps other cytokines induced by malaria as well as by viruses. This gives the first proposed explanation for Reye's syndrome, defining the circumstances in which it occurs, and predicting a rationale for its treatment. Through the parallels seen in different age groups in malaria and aspirin toxicity, it also rationalises the difference in childhood vs adult malaria syndromes. 3. The overall severity and mortality of childhood malaria in East Africa may be worsened, through this cytokine-salicylate synergy, by home treatment with aspirin when children first become ill. 4. A relative absence of salicylate intake by children in various malarial Pacific Islands may contribute to falciparum malaria being a less severe disease there than in East Africa.Read moreRead less
Role Of P2X7 In Innate And Adaptive Immunity To Mycobacterial Infections
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Tuberculosis remains an enormous global health problem. Some 32% of the world s population are infected, with over 2 million persons dying each year. It is not well understood why some infected individuals develop clinical disease yet others remain healthy, but many cases are due to reactivation of dormant organisms lying within a specialized white cell, the macrophage. We know that declining socio-economic conditions, HIV co-infection, and some genetic risk factors such as HLA type contribute t ....Tuberculosis remains an enormous global health problem. Some 32% of the world s population are infected, with over 2 million persons dying each year. It is not well understood why some infected individuals develop clinical disease yet others remain healthy, but many cases are due to reactivation of dormant organisms lying within a specialized white cell, the macrophage. We know that declining socio-economic conditions, HIV co-infection, and some genetic risk factors such as HLA type contribute to the likelihood of an individual developing disease, but current known factors are insufficient to fully account for the risk of an infected individual developing disease. We have recently shown that the tuberculosis bacteria can be killed by the addition of a natural compound, ATP, to infected macrophages. This process occurs when ATP activates the P2X7 receptor leading to mycobacterial killing. We have identified several polymorphisms (mutations) in the P2X7 receptor. In individuals with one particular polymorphism, designated A1513C, these people do not respond to ATP and do not kill tuberculosis using this pathway. TB patients who are heterozygous for the A1513C polymorphism show approximately a 50% reduction in mycobacterial killing. We have preliminary evidence that this A1513C polymorphism is expressed at an over represented frequency in TB patients we have tested, suggesting that having this polymorphism may increase your risk of developing tuberculosis. The aim of this project is two fold. One, we will investigate the functioning of this receptor, determining how the P2X7 receptor is activated and how it interacts with other molecules in the immune system to kill tuberculosis. Secondly we shall determine if polymorphisms in the P2X7 receptor are a risk factor for the development of tuberculosis and leprosy disease.Read moreRead less