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

结核病（TB）仍然是全球范围内的一个巨大问题，也是澳大利亚持续存在的健康问题。大多数结核病不是由于感染时的疾病，而是在从未根除生物体的人中潜伏感染的重新激活。这项研究将在小鼠中调查结核病最初是如何被包含在肺中以及如何重新激活的。所有感染TB的小鼠最初都能控制感染。T淋巴细胞被激活，T细胞和巨噬细胞被募集到肺中，迁移到肺组织中并包围感染的肺巨噬细胞形成肉芽肿。我们已经确定了在感染后早期进展为TB疾病的小鼠（早期进展株）和另一种进展较晚的菌株（晚期进展株）。在早期进展者中，淋巴细胞不能有效地募集到肺中，并且不会形成在晚期进展者菌株中看到的紧密肉芽肿。我们计划对这两种菌株进行详细的比较，观察细胞膜分子和可溶性信使分子（细胞因子和趋化因子）的差异，这些分子提供吸引细胞到肺并引导它们包围感染的肺巨噬细胞的信号。通过比较早期和晚期进展菌株中的事件，我们将发现初始和长期遏制所需的分子，以及导致肉芽肿破裂和疾病再激活的事件。此外，我们最近发现，一种细胞因子，肿瘤坏死因子（TNF），是必不可少的细胞迁移通过肺。通过比较正常小鼠和TNF缺乏小鼠，我们将研究TNF调节的下游效应，特别是引导细胞移动到肉芽肿的趋化因子信使。通过鉴定控制结核病所需的分子和细胞，我们计划设计改进的疫苗来预防结核病感染，并改进治疗方法来预防疾病复发。

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.