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
Cytokine And Macrophage Determinants Of Pulmonary Inflammation During Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$455,899.00
Summary
Tuberculosis (TB) infects 33% of the world, causing over 2 million deaths per year. TB disease causes damaging lung pathology and new therapies to treat the infection and moderate inflammation are urgently required. TNF is essential for immunity to TB, acting to modulate inflammation. This grant will determine how soluble and membrane- bound TNF regulate the cellular and cytokine control of TB pathology and may lead to new therapies to limit inflammation in TB and other inflammatory diseases.