Regulation of Macrophage Apoptosis by Anthrax Lethal Factor

炭疽致死因子对巨噬细胞凋亡的调节 吸入形式的炭疽杆菌是一种侵略性的病原体，是一种理想的武器 生物恐怖主义。在被肺泡巨噬细胞吞噬后，炭疽孢子发芽， 变成营养细菌。受感染的巨噬细胞迁移到局部淋巴结并死亡， 不能杀死细胞内的细菌。病人很快死于大面积败血症， 毒血症。巨噬细胞死亡是相关病理学的重要组成部分， 巨噬细胞耗尽的动物对炭疽毒素的致死作用具有抗性。 我们提出实验来研究信号转导途径有助于 巨噬细胞反应、巨噬细胞死亡以及宿主随后的死亡。这些 实验将在培养的人巨噬细胞系中进行， 从健康供体肺获得的巨噬细胞。另外，我们将使用一种新的体外器官 技术开发部分所述的人肺培养模型。我们将测试 MEK裂解的作用和TNF α信号转导对巨噬细胞的贡献 死亡最后，我们将研究巨噬细胞反应的差异， 暴露于两种B。炭疽毒素，这种情况可能发生在体内。

Regulation of macrophage apoptosis by anthrax lethal factor The inhalation form of Bacillus anthracis is an aggressive pathogen and is an ideal weapon for bioterrorism. After phagocytosis by alveolar macrophages, the anthrax spores germinate to become vegetative bacteria. Infected macrophages migrate to regional lymph nodes and die, but fail to kill the intracellular bacteria. Patients rapidly succumb to the massive septicemia and toxemia. Macrophage death is an essential component in the associated pathology, as macrophage-depleted animals are resistant to the Lethal affects of anthrax toxin. We propose experiments to investigate the signal transduction pathways contributing to macrophage responses, macrophage death, and to the subsequent death of the host. These experiments will be conducted in cultured human macrophage cell lines and lavaged macrophages obtained from healthy donor lungs. Additionally, we will use a novel in vitro organ culture model of human lung described in the technology development section. We will test the role of MEK cleavage and the contribution of TNFalpha signal transduction to the macrophage cell death. Lastly, we will investigate differences in macrophage responses following concomitant exposure to both B. anthracis toxins, a situation that likely occurs in vivo.