The Role Of The Innate Immune System In The Immunopathogenesis Of Malaria
Funder
National Health and Medical Research Council
Funding Amount
$82,554.00
Summary
Malaria is common worldwide, affecting 600 million people. As with many infectious diseases, it the severity of a malaria infection is not only dictated by the parasite, but also the body’s immune response to the infection. This study looks at cells that contribute to the immediate immune response in two major clinical syndromes of malaria affecting women and children: cerebral malaria and malaria of pregnancy. By understanding the immune response, we gain insights into how to limit disease.
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
Fine Positioning And Effector Function Of T Cells Recruited To The HCV Infected Liver
Funder
National Health and Medical Research Council
Funding Amount
$321,973.00
Summary
The majority of patients who become infected with hepatitis C virus (HCV) are unable to mount an effective immune response and clear the virus and therefore develop lifelong (chronic) infection. The persistence of virus in the liver of patients with chronic infection results in the recruitment of significant numbers of immune cells, notably T cells, from the bloodstream into the liver where they are involved in both viral control (but not viral clearance) and liver injury. The level of tissue in ....The majority of patients who become infected with hepatitis C virus (HCV) are unable to mount an effective immune response and clear the virus and therefore develop lifelong (chronic) infection. The persistence of virus in the liver of patients with chronic infection results in the recruitment of significant numbers of immune cells, notably T cells, from the bloodstream into the liver where they are involved in both viral control (but not viral clearance) and liver injury. The level of tissue injury observed and the speed of disease progression may be linked to the type of T cells recruited, their function, and their position in the liver. The aims of this project are to determine the factors involved in the fine positioning of T cells in the liver and establish a relationship between T cell recruitment, function, and progression of HCV disease in the liver.Read moreRead less
Dissecting The Role Of The Adipokine Leptin In Control Of The Inflammatory Response To Helicobacter Pylori
Funder
National Health and Medical Research Council
Funding Amount
$569,063.00
Summary
Helicobacter pylori is a bacterium that causes chronic gastric inflammation (gastritis), which may lead to cancer. Approximately 20% of Australians are infected. As part of the search for a human vaccine, we are attempting to understand the immune response against this bacterium. This study will investigate a novel observation that adipokines-small proteins produced by fat cells can regulate the actions of immune cells in the stomach and in this way determine whether vaccination works.
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