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

肺结核保护性免疫表达中的细胞迁移和肉芽肿形成

• 批准号: nhmrc : 137880
• 负责人: Dr Bernadette Saunders
• 金额: $ 14.14万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2001
• 资助国家: 澳大利亚
• 起止时间: 2001-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/cell-migration-granuloma-tuberculosis-lung/81578
• 关键词: Cell; migration; granuloma; formation; expression

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.

结核病仍然是世界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引起的，而是在从未根除过细菌的人体内潜伏感染的重新激活。这项研究将在小鼠中调查结核最初如何被控制在肺部以及如何发生再激活。所有感染结核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，迁移到肺组织，包围被感染的肺巨噬细胞形成肉芽肿。我们已经确定了感染后早期进展为结核病的小鼠（早期进展菌株）和另一种进展较晚的菌株（晚期进展菌株）。在早期进展中，淋巴细胞不像晚期进展株那样有效地募集到肺部，也不形成紧密的肉芽肿。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，这些分子提供信号，将细胞吸引到肺部并指导它们包围被感染的肺巨噬细胞。通过比较早期和晚期进展菌株的事件，我们将发现哪些分子是初始和长期遏制所必需的，哪些事件导致肉芽肿的分解和疾病的重新激活。此外，我们最近发现一种细胞因子，肿瘤坏死因子（TNF），是细胞通过肺迁移所必需的。通过比较正常小鼠和缺乏TNF的小鼠，我们将研究TNF调节的下游效应，特别是指导细胞运动到肉芽肿的趋化因子信使。通过确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，改进的治疗方法来防止疾病再激活。