Host Factors Influencing Anthrax Toxin Sensitivity

影响炭疽毒素敏感性的宿主因素

• 批准号: 6933086
• 负责人: Ana M Sanchez
• 金额: $ 2.16万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933086
• 关键词: anthrax; anthrax toxin; bacterial toxicology; biological signal transduction; bioterrorism /chemical warfare; cell line; chemical genetics; cytolysis; cytoprotection; drug discovery /isolation; genetic screening; genetic susceptibility; immunity; macrophage; predoctoral investigator; quantitative trait loci; small molecule; toll like receptor

DESCRIPTION (provided by applicant): Evidence has shown that anthrax lethal toxin (LeTx) is responsible for most disease symptoms and death due to B. anthracis infection. However, the precise molecular mechanism by which lethal toxin causes disease remains a mystery. Lethal factor (L.F), the catalytic component of LeTx, is a zinc-dependent protease that has been shown to cleave MAPKKs, thus disrupting signaling through the ERK, p38, and JNK pathways. LF is able to enter and cleave MAPKK in the various tested cell types, however, only murine macrophages were shown to be sensitive to toxin induced lysis in vitro. Furthermore, macrophages from certain inbred strains of mice are resistant to toxin, but can be sensitized if activated with bacterial components, presumably via toll like receptors (TLR). We are interested in uncovering cellular mechanisms that contribute to toxin sensitivity. Here, we propose experiments designed to elucidate TLR signaling involved in sensitization of resistant macrophages as we predict this involves events that play a role upstream of toxin activity. Additionally, we will conduct somatic cell and chemical genetic screens using a toxin sensitive macrophage cell line to identify cellular factors or processes that play a role LF sensitivity.

描述（由申请人提供）：证据表明，炭疽致死毒素（LeTx）是导致B引起的大多数疾病症状和死亡的原因。炭疽感染。然而，致命毒素导致疾病的精确分子机制仍然是一个谜。致死因子（L.F.）是LeTx的催化组分，是一种锌依赖性蛋白酶，其已被证明可切割MAPKKs，从而破坏通过ERK、p38和JNK途径的信号传导。LF能够进入并切割各种测试细胞类型中的MAPKK，然而，仅显示鼠巨噬细胞对毒素诱导的体外裂解敏感。此外，来自某些近交系小鼠的巨噬细胞对毒素具有抗性，但如果用细菌组分激活，可能通过Toll样受体（TLR）激活，则可以致敏。我们有兴趣揭示有助于毒素敏感性的细胞机制。在这里，我们提出的实验旨在阐明TLR信号参与敏化抗性巨噬细胞，因为我们预测这涉及的事件，发挥作用的毒素活性的上游。此外，我们将使用毒素敏感的巨噬细胞系进行体细胞和化学遗传筛选，以鉴定发挥LF敏感性作用的细胞因子或过程。