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
Visualisation Of Gamma-delta T Cell Responses In Cutaneous Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$570,876.00
Summary
Mycobacterial infections remain a major burden of modern society. This proposal aims to define the role of an understudied immune cell subset, gamma-delta T cells, in the response against mycobacteria. We will use cutting-edge multi-photon imaging to track these cells in real-time directly within infected tissues. This will facilitate generating a new vista of anti-mycobacterial immune responses and may aid the development of improved vaccines.
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
A Unique Network Of Phagocytic Cells At The Interface Between The Liver And Peritoneal Cavity
Funder
National Health and Medical Research Council
Funding Amount
$787,521.00
Summary
This project aims to characterise the nature and ontogeny of a novel population of cells with phagocytic capacity that forms a network underlying the capsule of mouse and human liver reminiscent of that formed by Langherans cells in the epidermis of the skin. In this project we will characterise this newly described liver capsular macrophage subset, define their ontogeny and assess their specific functions.
Discovery Of New Tuberculosis Drug Leads Targeting Cell Wall Biosynthesis
Funder
National Health and Medical Research Council
Funding Amount
$714,816.00
Summary
There is a desperate need for the development of new therapies for the treatment of TB due to widespread resistance of Mycobacterium tuberculosis, the causative agent of TB, to current therapies. The overall goal of this research project is to identify new TB drug leads through the development of structural analogues of bacterially-derived natural products called the sansanmycins that inhibit cell wall synthesis in Mycobacterium tuberculosis.
The Emerging Problem Of Non-tuberculous Mycobacteria Infection: Understanding Aetiology, Geospatial Epidemiology And Developing Interventions
Funder
National Health and Medical Research Council
Funding Amount
$988,791.00
Summary
This project will be largest study of non-tuberculous mycobacterial (NTM) infection in cystic fibrosis. By combining growing the bacteria with detailed information from the CF patient data registry, geographical location and environmental conditions, this study will provide novel insights into factors associated with NTM. Gene sequencing and airway infection profiling will extend understanding and has the potential to identify novel risk factors and biomarkers for NTM-related airways disease.
A New Class Of Inhibitors For The Treatment Of Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$720,691.00
Summary
Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, with 1.3 million deaths annually. Some strains of the TB bacterium are resistant to all available drugs. We have identified novel chemical structures that display potent and specific activity against pathogenic mycobacteria. In this proposal we will develop optimised derivatives with more potent activity against mycobacteria, assess their stability and toxicity and determine their mode of action.
Mycobacterial Control Of The Establishment And Outcome Of Infection
Funder
National Health and Medical Research Council
Funding Amount
$311,956.00
Summary
Tuberculosis (TB) claims almost two million lives every year. TB subverts host immunity by directing the immune cells to launch an ineffective response to infection. One such trick is to hijack control of a class of molecules called eicosanoids from the host. This project will use a validated zebrafish model of TB infection to pinpoint the mechanisms used by mycobacteria to subvert normal eicosanoid production. Findings from this work may to aid the creation of novel anti-TB therapies.
Buruli ulcer (BU) is a destructive skin and soft tissue infection that can cause permanent deformity. Australian native possums carry in their guts the bacteria that causes BU and mosquitoes spread BU to people from areas contaminated by possum faeces. A targeted intervention based on screening possum faeces followed by control of mosquitoes in areas where possums and mosquitoes are shown to carry the bacteria will be trialed here, giving public health officials a means to stop this disease.
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