MECHANISMS AND MARKERS OF TUBERCULOSIS TRANSMISSION WITHIN AUSTRALIA
Funder
National Health and Medical Research Council
Funding Amount
$799,978.00
Summary
Tuberculosis (TB) kills nearly 2 million people each year. The emergence of drug resistant TB in the Asia-Pacific region poses a particular threat to Australia, due to frequent population mixing and ongoing TB transmission that may facilitate its spread within vulnerable communities. The proposed study will develop advanced tools to monitor and limit TB transmission within Australia. It will also provide novel insight into the evolution of the global TB epidemic and key factors that sustain it.
Regulation From The Outside: Control Of Transport And Assembly Of Major Cell Wall Components In Mycobacteria
Funder
National Health and Medical Research Council
Funding Amount
$652,019.00
Summary
Tuberculosis (TB) kills nearly two million people each year while the causative bacterial species, Mycobacterium tuberculosis, infects one-third of the entire human population. An alarmingly high rate of TB exists in Australia's indigenous population. This proposal aims to identify and characterise essential processes that regulate synthesis of the outer coat of the bacterium, which are potential targets for new drugs for the treatment of this devastating disease.
Cell Migration And Granuloma Formation In The Expression Of Protective Immunity Against Tuberculosis In The Lung
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Tuberculosis (TB) remains an enormous problem worldwide and a continuing health problem in Australia. Most TB is not due to disease at the time of infection, but is a reactivation of dormant infection in people who have never eradicated the organisms. This study will investigate, in mice, how TB is initially contained within the lungs and how reactivation occurs. All mice infected with TB control the infection initially. T lymphocytes are activated and T cells and macrophages are recruited to th ....Tuberculosis (TB) remains an enormous problem worldwide and a continuing health problem in Australia. Most TB is not due to disease at the time of infection, but is a reactivation of dormant infection in people who have never eradicated the organisms. This study will investigate, in mice, how TB is initially contained within the lungs and how reactivation occurs. All mice infected with TB control the infection initially. T lymphocytes are activated and T cells and macrophages are recruited to the lung, migrate into lung tissue and surround infected lung macrophages forming granulomas. We have identified mice that progress to TB disease early after infection (early progressor strains) and another strain that progresses later (late progressors). In the early progressors, lymphocytes are not as efficiently recruited to the lung and do not form the tight granulomas seen in late progressor strains. We plan to make a detailed comparison of these two strains looking at differences in cell-membrane molecules and the soluble messenger molecules (cytokines and chemokines) that provide the signals that attract cells to the lung and direct them to surround infected lung macrophages. By comparing events in early and late progressor strains we will find which molecules are required for initial and long-term containment, and which events lead to breakdown of granulomas and reactivation of disease. In addition, we recently showed that one cytokine, tumour necrosis factor (TNF), is essential for cell migration through the lung. By comparing normal mice with mice deficient in TNF we will study the downstream effects regulated by TNF, particularly the chemokine messengers that direct cell movement into granulomas. By identifying the molecules and cells required to control TB we plan to design improved vaccines to prevent TB infection and improved treatments to prevent disease reactivation.Read moreRead less
Membrane TNF And Lymphotoxin Control Of Chemokine Induction And Inflammation In Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
Tuberculosis (TB) remains an enormous problem worldwide. Most TB is not due to disease at the time of infection, but is a reactivation of dormant disease in people who have never completely eradicated the organisms. Macrophages containing dormant TB organisms are located in lesions called granulomas. Granulomas consist of TB-infected macrophages surrounded by T lymphocytes that actively contain the infection. T lymphocytes prevent the growth of TB organisms in the macrophages and so prevent wide ....Tuberculosis (TB) remains an enormous problem worldwide. Most TB is not due to disease at the time of infection, but is a reactivation of dormant disease in people who have never completely eradicated the organisms. Macrophages containing dormant TB organisms are located in lesions called granulomas. Granulomas consist of TB-infected macrophages surrounded by T lymphocytes that actively contain the infection. T lymphocytes prevent the growth of TB organisms in the macrophages and so prevent widespread infection that would cause illness in the host. Activated T lymphocytes that recognise TB-infected macrophages circulate in blood, are recruited from blood capillaries into the lung, migrate through the tissue and co-localise with infected macrophages. Soluble molecules (cytokines and chemokines) are known to provide the signals that direct cell migration and activation events. This study will investigate in detail cytokines and chemokines that are involved, the cells that produce then and where these cells are located in the lung. We recently showed that tumour necrosis factor (TNF), and the related cytokine lymphotoxin (LT), are essential for lymphocyte migration through the lung. These belong to a family of related molecules that signal through the same panel of receptors and regulate chemokine expression and inflammation. In this study we will use genetically manipulated mice that lack TNF. LT or other family members or that express only membrane-bound TNF to study how each affects production of different chemokines, chemokine receptors and other molecules. Since there are at least 50 known chemokines and 17 chemokine receptors we will use microarray technology to simultaneously screen changes in expression of several thousand genes and laser microdissection to study cells from different location in infected lungs. Understanding signals necessary to direct T cells into granulomas may facilitate new treatments to prevent TB reactivation disease.Read moreRead less
Investigating The Mechanisms Of Regulation Of Mycobacterial Cell Wall Biosynthesis
Funder
National Health and Medical Research Council
Funding Amount
$597,349.00
Summary
Tuberculosis (TB) kills around two million people each year while the causative bacterial species, Mycobacterium tuberculosis, infects one-third of the entire human population. An alarmingly high rate of TB exists in Australia's indigenous population. This proposal aims to identify and characterise essential processes involved in synthesis of the outer coat of the bacterium which are potential targets for new drugs for the treatment of this devastating disease.
Human Genetic Susceptibility To Pulmonary Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$760,432.00
Summary
Tuberculosis (TB) infects about a third of the world population, causing significant disease in 10% of infected individuals. We propose to undertake a genome-wide study to investigate human susceptibility to this devastating disease. Identifying novel gene associations from this study may explain why some people are more vulnerable to TB. Understanding these processes may lead to more effective treatments which is essential for the long term control of disease not only in China, but worldwide
Genetic Adaptations Of Mycobacterium Tuberculosis For Intracellular Survival
Funder
National Health and Medical Research Council
Funding Amount
$187,677.00
Summary
Tuberculosis (TB) remains a significant global public health problem and new approaches to its treatment and prevention are urgently needed. The disease is caused by infection with Mycobacterium tuberculosis, a slow growing organism that lives within cells. How it adapts to survive in this intracellular environment is unknown. Recently the complete genome of M. tuberculosis was sequenced and new techniques developed for manipulating its genes. We plan to use these techniques to identify genes th ....Tuberculosis (TB) remains a significant global public health problem and new approaches to its treatment and prevention are urgently needed. The disease is caused by infection with Mycobacterium tuberculosis, a slow growing organism that lives within cells. How it adapts to survive in this intracellular environment is unknown. Recently the complete genome of M. tuberculosis was sequenced and new techniques developed for manipulating its genes. We plan to use these techniques to identify genes that are more active within the cells. Genes are controlled by short sequences of preceding DNA called promoters. If these promoters are randomly placed in front of readily identifiable reporter genes and inserted into a suitable host strain, it is possible to select for those promoters expressed only inside cells and then identify the promoter and its gene by sequence analysis. We plan to use two types of reporter genes. First, we shall place the M. tuberculosis DNA containing promoters before the gene for a naturally fluorescent protein within the M. bovis BCG host strain and then infect macrophages. If the promoters are switched on inside the cell, the macrophages will become green and can be selected and the promoter identified. After several rounds of selection the promoter is isolated and identified. Second, we shall select the promoters by their ability to produce a protein that is on the surface of the bacterium. We will use these intracellular genes to make better vaccines against TB. Genes that enhance intracellular survival may contribute to the virulence of the TB organism. By removing these genes we can make an attenuated organism suitable as a vaccine. We will test for reduced virulence by growth inside cells in mice. We will also use the intracellular promoter to improve the current BCG vaccine. Proteins expressed inside the cell may also be targets for new TB drugs.Read moreRead less