Molecular Mechanisms of Anthrax-Induced Macrophage Death

炭疽引起巨噬细胞死亡的分子机制

• 批准号: 6846267
• 负责人: Jiahuai Han
• 金额: $ 37.54万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846267
• 关键词: Bacillus anthracis; anthrax; anthrax toxin; bacteria infection mechanism; bacterial cytopathogenic effect; bacterial toxins; cell death; gel mobility shift assay; host organism interaction; laboratory mouse; leukocyte activation /transformation; macrophage; metalloendopeptidases; western blottings

DESCRIPTION (provided by applicant): Exotoxins produced by anthrax bacilli are believed to be responsible for overt shock symptoms and death in infected animals. Cytolysis of macrophages caused by anthrax lethal toxin (LeTx) is a trigger of shock symptoms and death. LeTx can directly lyse macrophages of some mouse strains. However, the sensitivity of different murine macrophages to LeTx in vitro does not correlate with in vivo susceptibility of corresponding strains to B. anthracis. This suggests that there are factors other than LeTx also contributing to the cytolysis of macrophages. The death of LeTx-resistant macrophages needs to be studied because LeTx alone cannot kill human macrophages in vitro. The long-term goal of our study is to understand the molecular mechanisms that lead to the death of LeTx-resistant macrophages in anthrax infection. We have found that treatment of macrophages with bacterial components can make LeTx-resistant macrophages became sensitive to LeTx-induced cytolysis, suggesting that the death of LeTx-resistant macrophages requires two stimuli. We further determined that tumor necrosis factor-alpha (TNF) induced by bacterial components is at least one of the factors that can cooperate with LeTx in inducing macrophage death. In addition, mTor (mammalian target of rapamycin) signaling was found to be required for the death of LeTx-resistant macrophages. Although anthrax bacilli can escape phagocytosis by macrophages, they should activate macrophages to certain levels. We believed the autocrine effect of TNF plays a key role in LeTx-resistant macrophage death in vivo. In supporting this notion, it has been reported that administration of anti- TNF antibody improved survival of anthrax-infected C57BL/6 mice. This proposal will focus on the mechanisms of the cell death in LeTx-resistant macrophages. The death of LeTx-resistant macrophages will be addressed from the side of macrophage activation. The signaling pathways that cooperatively operate in causing LeTx-resistant macrophage death will be elucidated by biochemical and molecular biology approaches. The information obtained in this study will be very valuable in developing new strategies for the treatment of anthrax infection.

描述（由申请人提供）：据信由炭疽杆菌产生的外毒素是导致感染动物的明显休克症状和死亡的原因。由炭疽致死毒素（LETX）引起的巨噬细胞的细胞解析是减震症状和死亡的触发因素。 LETX可以直接裂解某些小鼠菌株的巨噬细胞。但是，不同鼠巨噬细胞对体外LETX的敏感性与相应菌株与炭疽芽孢杆菌的体内敏感性无关。这表明除了LETX外，还有其他因素也导致了巨噬细胞的细胞解析。需要研究耐LETX巨噬细胞的死亡，因为单独的letx不能在体外杀死人类巨噬细胞。我们研究的长期目标是了解导致炭疽感染中耐LETX抗巨噬细胞死亡的分子机制。我们发现，用细菌成分对巨噬细胞的处理可以使抗LETX抗性巨噬细胞对LETX诱导的胞溶敏感，这表明耐LETX耐药的巨噬细胞的死亡需要两个刺激。我们进一步确定细菌成分诱导的肿瘤坏死因子-Alpha（TNF）至少是可以与LETX合作诱导巨噬细胞死亡的因素之一。此外，发现MTOR（乳中霉素的哺乳动物靶标）信号传导是耐LETX抗巨噬细胞死亡所必需的。尽管炭疽杆菌可以通过巨噬细胞避免吞噬作用，但它们应将巨噬细胞激活到某些水平。我们认为，TNF的自分泌作用在体内抗LETX抗巨噬细胞死亡中起关键作用。在支持这一概念时，据报道，抗TNF抗体的给药可改善感染的C57BL/6小鼠的存活率。该提案将重点介绍耐LETX巨噬细胞中细胞死亡的机制。抗LETX抗巨噬细胞的死亡将从巨噬细胞激活的一侧解决。通过生化和分子生物学方法阐明了在引起抗LETX抗巨噬细胞死亡方面合作运作的信号传导途径。在这项研究中获得的信息对于制定炭疽感染的新策略将非常有价值。