Mannose Receptor in Ricin Pathogenesis

描述（由申请人提供）：蓖麻毒素是已知的毒性最强的生物制剂之一。该提案将验证一种假设，即甘露糖受体（MR），一种通常被认为在先天免疫中起作用的c型凝集素，介导蓖麻毒素进入肝脏和脾脏的巨噬细胞，从而引发炎症和细胞死亡，这是与蓖麻毒素中毒相关的最早和最严重的影响。将使用MR敲除（MR-/-）小鼠，结合已建立的蓖麻毒素致死剂量挑战方案，对该假设进行验证。为了确定MR对蓖麻毒素体内毒性的影响，Specific Aim 1将比较野生型和MR-/-型小鼠蓖麻毒素的中位致死剂量。特异性目标2将确定MR在清除血清中的蓖麻毒素，并将毒素靶向肝脏和脾脏中的作用。最后，Specific Aim 3将确定MR在介导毒素诱导的脾脏和肝脏细胞凋亡和炎症中的作用。这项研究有望揭示致病因子如蓖麻毒素利用MR绕过正常宿主防御机制并进入宿主细胞亚群的基本机制。该研究还将提供必要的关键信息，以开发干扰中毒过程早期步骤的蓖麻毒素抑制剂，并因此将推进NIAID的使命，开发针对B类选择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的毒素，被疾病控制中心和国立卫生研究院认为是潜在的生物恐怖主义制剂。本研究旨在探讨蓖麻毒素如何进入细胞并引起疾病。这项研究的结果有望产生新的见解，设计一种有效的解毒剂对抗这种致命的毒素。

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.