Cell migration and granuloma formation in the expression of protective immunity against tuberculosis in the lung

点击翻译按钮获取中文摘要

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.