Mannose Receptor in Ricin Pathogenesis

甘露糖受体在蓖麻毒素发病机制中的作用

• 批准号: 7876804
• 负责人: Nicholas J. Mantis
• 金额: $ 17.88万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876804
• 关键词: Affect; Affinity; Antidotes; Apoptosis; Biological Products; Biology; Bioterrorism; Blood Circulation; Bypass; C-Type Lectins; Categories; Cell Death; Cell surface; Cells; Centers for Disease Control and Prevention (U.S.); Cytoplasm; Cytosol; Development; Disease; Dose; Endocytosis; Endothelial Cells; Functional disorder; Galactose; Glycolipids; Glycoproteins; Hepatic; Host Defense; Host Defense Mechanism; Immune system; In Vitro; Inflammation; Institutes; Intoxication; Knock-out; Kupffer Cells; Lactose; Lectin; Link; Liver; Mannose; Mediating; Mission; Monoclonal Antibodies; Mus; Natural Immunity; Organ; Pathogenesis; Pathway interactions; Poisoning; Population; Process; Proteins; Protocols documentation; Ribosomes; Ricin; Role; Serum; Side; Spleen; Targeted Toxins; Testing; Time; Toxic effect; Toxin; Universities; Viral; design; in vivo; inhibitor/antagonist; insight; intravenous injection; killings; macrophage; mannose receptor; microorganism antigen; prevent; public health relevance; receptor; uptake

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.

描述(申请人提供)：蓖麻毒素是已知的毒性最大的生物制剂之一。该提案将检验一种假设，即甘露糖受体(MR)是一种C型凝集素，通常被认为在先天性免疫中起作用，它介导蓖麻毒素进入肝脏和脾的巨噬细胞，从而引发炎症和细胞死亡，导致与蓖麻毒素中毒相关的最早和最严重的影响。这一假设将使用MR基因敲除(MR-/-)小鼠进行验证，并结合公认的蓖麻毒素致死剂量挑战方案。为了确定MR在蓖麻毒素体内毒性中的作用，特异靶1将比较野生型和MR-/-小鼠的蓖麻毒素半数致死剂量。具体目标2将确定MR在清除血清中的蓖麻毒素和将毒素靶向肝脏和脾方面的贡献。最后，特定的目标3将确定MR在介导毒素诱导的脾和肝脏的细胞凋亡和炎症中的作用。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。这项研究还将为开发干扰中毒过程中最早步骤的蓖麻毒素抑制剂提供必要的关键信息，因此将推动NIAID开发针对B类精选制剂和毒素的有效对策的使命。与公共健康相关：蓖麻毒素是一种致命的毒素，被疾病控制中心和美国国立卫生研究院认为是一种潜在的生物恐怖分子。这项研究建议调查蓖麻毒素是如何进入细胞并导致疾病的。这项研究的结果有望对这种致命毒素的有效解毒剂的设计产生新的见解。

项目成果

Role of the mannose receptor (CD206) in innate immunity to ricin toxin.

• DOI: 10.3390/toxins3091131
• 发表时间: 2011-09
• 期刊: Toxins
• 影响因子: 4.2
• 作者: Gage E;Hernandez MO;O'Hara JM;McCarthy EA;Mantis NJ
• 通讯作者: Mantis NJ