Mannose Receptor in Ricin Pathogenesis

描述（由申请人提供）：蓖麻毒素是已知毒性最强的生物制剂之一。该提案将检验以下假设：甘露糖受体（MR）是一种通常被认为在先天免疫中发挥作用的C型凝集素，介导蓖麻毒素被肝脏和脾脏中的巨噬细胞吸收，从而引发炎症和细胞死亡，从而导致与蓖麻毒素中毒相关的最早和最严重的影响。该假设将使用 MR 敲除 (MR-/-) 小鼠并结合完善的蓖麻毒素致死剂量挑战方案进行测试。为了确定 MR 对蓖麻毒素体内毒性的影响，特定目标 1 将比较野生型和 MR-/- 小鼠中蓖麻毒素的半数致死剂量。具体目标 2 将确定 MR 在清除血清中的蓖麻毒素以及将毒素靶向肝脏和脾脏方面的贡献。最后，具体目标 3 将确定 MR 在介导毒素诱导的细胞凋亡和脾脏和肝脏炎症中的作用。这项研究有望揭示蓖麻毒素等病原体利用 MR 绕过正常宿主防御机制并进入选定的宿主细胞亚群的基本机制。这项研究还将提供开发干扰中毒过程最早步骤的蓖麻毒素抑制剂所需的关键信息，因此将推进 NIAID 的使命，即制定针对 B 类精选药剂和毒素的有效对策。公共卫生相关性：蓖麻毒素是一种致命毒素，被疾病控制中心和美国国立卫生研究院认为是潜在的生物恐怖主义剂。这项研究旨在调查蓖麻毒素如何进入细胞并引起疾病。这项研究的结果预计将为设计针对这种致命毒素的有效解毒剂提供新的见解。

DESCRIPTION (provided by applicant): Ricin is one of the most toxic biological agents known. The proposal will test the hypothesis that the mannose receptor (MR), a C-type lectin normally assumed to function in innate immunity, mediates the uptake of ricin into macrophages in the liver and spleen, and thereby initiates the inflammation and cell death responsible for the earliest and most severe affects associated with ricin poisoning. The hypothesis will be tested using MR knock- out (MR-/-) mice, in conjunction with well-established ricin lethal dose challenge protocols. To determine the effect of the MR in the toxicity of ricin in vivo, Specific Aim 1 will compare the median lethal dose of ricin in wild type and MR-/- mice. Specific Aim 2 will determine the contribution of the MR in clearing ricin from the serum, and targeting the toxin to the liver and spleen. Finally, Specific Aim 3 will identify the role of the MR in mediating toxin-induced apoptosis and inflammation in the spleen and liver. This study is expected to uncover fundamental mechanisms by which pathogenic agents such as ricin toxin exploit the MR to bypass normal host defense mechanisms and gain entry into select sub-populations of host cells. This study will also provide critical information necessary to develop inhibitors of ricin that interfere with the earliest steps in the intoxication process, and will, therefore, advance NIAID's mission to develop effective countermeasures against the Category B Select Agents and Toxins. PUBLIC HEALTH RELEVANCE: Ricin is a deadly toxin that is considered a potential bioterrorism agent by the Centers for Diseases Control and the National Institutes of Heath. This study proposes to investigate how ricin toxin enters into cells and causes disease. The results of this study are expected to yield new insights the design of an effective antidote against this deadly toxin.