Genetics And Biochemistry Of Biosynthesis Of The Cell Wall Of Mycobacteria
Funder
National Health and Medical Research Council
Funding Amount
$260,831.00
Summary
Mycobacteria commolnly cause human disease. The major killer in the group is Mycobacterium tuberculosis which annually causes millions of deaths from tuberculosis (TB) worldwide. Another pathogen from this group is Mycobacterium avium which often infects immunosuppressed people such as those with advanced HIV-AIDS. Mycobacteria have evolved a specialised wall that surrounds their cells which protects them from chemical attack from antibiotics and helps them to establish infections. The major ant ....Mycobacteria commolnly cause human disease. The major killer in the group is Mycobacterium tuberculosis which annually causes millions of deaths from tuberculosis (TB) worldwide. Another pathogen from this group is Mycobacterium avium which often infects immunosuppressed people such as those with advanced HIV-AIDS. Mycobacteria have evolved a specialised wall that surrounds their cells which protects them from chemical attack from antibiotics and helps them to establish infections. The major antibiotic used for TB stops cells from synthesising the protective layer thereby making them very vulnerable to human immune defences. Unfortunately, resistance to this antibiotic is common and new antibiotics are needed to treat mycobacterial infections. We are studying how mycobacteria make the cell wall and are looking for key steps where new drugs might be able to inhibit the process. Our approach is to inactivate genes in the mycobacteria that make the enzymes which control cell wall synthesis. The gene inactivation results in crippled mycobacteria that are unable to make proper cell walls. We analyse the cell wall changes that gene inactivation cause studying the chemical composition of the cell. This helps to identify the steps in cell wall biosynthesis and each step becomes a potential target for new drugs. Each of the weaken mycobacteria can be tested to see how well they can resist antibiotics and to see if they can survive host defences. In this way we can identify which components of the cell wall are critical for them to establish infections and resist antibiotic treatments. Enzymes that participate in the synthesis of such components are prime targets for us to concentrate on to design new antibiotics.Read moreRead less
KILLING OF MYCOBACTERIUM TUBERCULOSIS IN MACROPHAGES VIA THE P2X7 RECEPTOR
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
Tuberculosis remains an enormous global health problem. Some 32% of the world population are infected, with over 1 million persons dying each year. The risk of an infected individual developing clinical disease ranges from 2-23% for their lifetime. We know that both environmental factors, such as declining socio-economic conditions, and genetic risk factors such as HLA type contribute to the likelihood of an individual developing disease, but current known factors are insufficient to fully accou ....Tuberculosis remains an enormous global health problem. Some 32% of the world population are infected, with over 1 million persons dying each year. The risk of an infected individual developing clinical disease ranges from 2-23% for their lifetime. We know that both environmental factors, such as declining socio-economic conditions, and 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 attributed to genetics. The aim of this project is to investigate another potential risk factor involved in the development of tuberculosis, that of P2X7 receptor function. A natural compound, ATP, when added to macrophages is able to kill tuberculosis organisms residing within the macrophage. This process occurs when ATP activates the P2X7 receptor. We have recently identified a mutation in the P2X7 receptor, which causes a loss of receptor function. Individuals who have this mutation are unable to respond to ATP and hence may be unable to kill tuberculosis. Our studies will determine if the mutation we have identified in the P2X7 receptor prevents or inhibits ATP mediated killing of mycobacteria. Furthermore we will determine the frequency of this mutation in TB patients and the general population to determine if this mutation in the P2X7 receptor is a risk factor for the development of tuberculosis disease.Read moreRead less
Regulation Of Pulmonary Immune Responses To Subunit Vaccines Against Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$509,202.00
Summary
Tuberculosis (TB) remains an enormous health problem world-wide. Improving the effectiveness of anti-TB vaccines is essential for its control. The first approach to improving subunit TB vaccines will be to manipulate the cellular immune response to the vaccine by increasing the positive cytokine signals, or reducing inhibitory effects on the immune response. The second approach is to develop new subunit vaccines to deliver to the lung in order to increase the potency of the protective response.
Chronic Bacterial Infection And The Generation Of T Cell Memory: Implication For Vaccination Against Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Two million people die from tuberculosis (TB) each year. The immune system is unable to eradicate the TB bacterium, and the type of immune response needed to protect against the disease is poorly understood. We will use animal models of TB infection and sophisticated immunological techniques to decipher how the TB bacterium interacts with the immune sytem and causes disease. We will also develop new TB vaccines that aim to boost the immune response in the lung, the main site of TB infection.
Attenuated And Recombinant Mycobacterial Strains As Novel Vaccines To Control Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$370,500.00
Summary
Tuberculosis is a major worldwide health problem. Around one third of the world s population is infected with the bacterium that causes tuberculosis, which results in 2 million deaths per year. Furthermore, people infected with the AIDS virus are at a much greater risk of catching tuberculosis. The only vaccine available for tuberculosis, known as BCG, is not very effective at preventing the disease. Therefore there is an urgent need to develop new vaccines to help combat tuberculosis. This proj ....Tuberculosis is a major worldwide health problem. Around one third of the world s population is infected with the bacterium that causes tuberculosis, which results in 2 million deaths per year. Furthermore, people infected with the AIDS virus are at a much greater risk of catching tuberculosis. The only vaccine available for tuberculosis, known as BCG, is not very effective at preventing the disease. Therefore there is an urgent need to develop new vaccines to help combat tuberculosis. This project aims to develop and test novel vaccines to prevent tuberculosis. We will produce forms of the existing BCG vaccine that have been altered to boost the components of the immune system needed to provide optimal protection against tuberculosis. Other potential vaccines that we will test are very similar to the bacterium that causes tuberculosis but have been altered such that they do not cause disease. Using animal models of tuberculosis and sophisticated immunological techniques we wish to determine if these live vaccines can stimulate the right type of immune response needed to fight tuberculosis and prevent infection. This is an internationally competitive project and our team is at the forefront of this research effort. A new, effective tuberculosis vaccine would be a major medical breakthrough and a represent a significant achievement for Australian health and medical research.Read moreRead less
Molecular Approaches To Developing Subunit Vaccines With Improved Efficacy Against Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
Tuberculosis remains a major worldwide health problem, resulting in approximately 3 million deaths per year. Furthermore, people infected with the AIDS virus are at a much greater risk of catching tuberculosis. The only vaccine available for tuberculosis, known as BCG, is not very effective at preventing the disease. Therefore there is an urgent need to develop new vaccines to help combat tuberculosis. The bacterium that causes tuberculosis is made up of may proteins, some of which are known to ....Tuberculosis remains a major worldwide health problem, resulting in approximately 3 million deaths per year. Furthermore, people infected with the AIDS virus are at a much greater risk of catching tuberculosis. The only vaccine available for tuberculosis, known as BCG, is not very effective at preventing the disease. Therefore there is an urgent need to develop new vaccines to help combat tuberculosis. The bacterium that causes tuberculosis is made up of may proteins, some of which are known to induce immune responses in animals and humans. We will produce vaccines that are made from 13 of these important proteins. Using a laboratory animal model that closely mimics human tuberculosis infection, together with sophisticated immunological techniques, we will determine if these vaccines stimulate the right immune response to fight tuberculosis and prevent infection. In addition, we will exploit molecules known to boost immune responses to optimise these vaccines. Further we will study the recently sequenced genome of the tuberculosis bacterium to identify new proteins that may be included in these novel anti-tuberculosis vaccines. This is an internationally competitive project and our team is at the forefront of this research effort. A new, effective tuberculosis vaccine would be a major medical breakthrough and a represent a significant achievement for Australian health and medical research.Read moreRead less