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Copper and iron in nutritional immunity

铜和铁在营养免疫中的作用

基本信息

批准号：
10308477
负责人：
MICHAEL J. PETRIS
金额：
$ 41.88万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-17 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308477
关键词：
Acute-Phase Proteins Anemia Bacterial Infections Biochemical Genetics Blood Brain Carrier Proteins Cause of Death Cell membrane Centers for Disease Control and Prevention (U.S.)Ceruloplasmin Copper Critical Illness Data Enterocytes Exhibits Genes Goals Hepatic Hepatocyte Homeostasis Hormones Host Defense Hypersensitivity Immune response Immunity Infection Innate Immune System Ions Iron Iron Overload Knock-out Knockout Mice Lead Ligands Link Liver Mediating Metals Mus Natural Immunity Nutrient Nutritional Immunity Pancreas Patients Plasma Play Predisposition Process Proteins Receptor Signaling Reporting Role Salmonella typhimurium Serum Staphylococcus aureus Systemic infection Testing Toll-like receptors Transferrin Yersinia pestis bactericide cell type cytokine effective therapy fighting genetic approach hepcidin hypercupremia loss of function mutation macrophage metal transporting protein 1 microbial novel oxidation pathogenic bacteria peptide hormone prevent response

项目摘要

The objective of this proposal is to elucidate the mechanisms by which the coppercontaining ferroxidase, ceruloplasmin, regulates nutritional immunity against bacterial infection. There is an urgent need to understand mechanisms of nutrient homeostasis in order to develop more effective treatments and therapies. Nutritional immunity describes mechanisms that alter host metal ion homeostasis during microbial infection. An important aspect of nutritional immunity is iron withholding from bacterial pathogens via hypoferremia (low plasma iron levels). Hypoferremia is regulated by peptide hormone, hepcidin, which restricts iron export into the plasma by inducing the degradation of the iron exporter, ferroportin in hepatocytes, enterocytes and macrophages. Another mechanism of nutritional immunity involves hypercupremia (high plasma copper levels). This process occurs via increased hepatic secretion of ceruloplasmin, a copper carrying ferroxidase that contains the majority of copper in the plasma. Copper is thought to facilitate killing of bacterial pathogens via macrophages of the innate immune system, however, the role of ceruloplasmin in this process is unknown. Despite its identification as an acute phase protein more than 60 years ago, the requirement for ceruloplasmin during infection remains unknown. As a ferroxidase, ceruloplasmin facilitates iron export via ferroportin, however, this function is unnecessary during infection due to ferroportin degradation. Thus, it is likely that ceruloplasmin has alternative functions during infection. Preliminary results demonstrate that ceruloplasmin knockout mice are highly susceptible to systemic infection by the bacterial pathogens Salmonella typhimurium and Staphylococcus aureus. In addition, ceruloplasmin knockout mice were found to exhibit reduced serum levels of proinflammatory cytokines when challenged with bacterial ligands to Tolllike receptors (TLRs), highlighting a possible role for ceruloplasmin in TLR signaling. In this proposal, biochemical and genetic approaches will be used to understand the contribution of ceruloplasmin to nutritional immunity. AIM1 tests the role of iron and copper on hypersensitivity of ceruloplasmin-null mice to infection. AIM 2 seeks to understand the role of ceruloplasmin in TLR signaling within macrophages. AIM 3 investigates whether macrophage or hepatocyte expression of ceruloplasmin is required for host immunity.

该提案的目的是阐明含铜亚铁氧化酶、铜蓝蛋白调节针对细菌感染的营养免疫的机制。迫切需要了解营养稳态的机制，以便开发更有效的治疗方法。营养免疫描述了微生物感染期间改变宿主金属离子稳态的机制。营养免疫的一个重要方面是通过低铁血症（低血浆铁水平）抑制细菌病原体的铁。低铁血症由肽激素铁调素调节，铁调素通过诱导肝细胞、肠上皮细胞和巨噬细胞中的铁输出蛋白、铁转运蛋白的降解来限制铁输出到血浆中。营养免疫的另一种机制涉及高铜血症（高血浆铜水平）。这一过程是通过肝脏分泌铜蓝蛋白增加而发生的，铜蓝蛋白是一种携带铜的亚铁氧化酶，血浆中含有大部分铜。铜被认为有助于通过先天免疫系统的巨噬细胞杀死细菌病原体，然而，铜蓝蛋白在此过程中的作用尚不清楚。尽管 60 多年前就已将其鉴定为急性期蛋白，但感染过程中对铜蓝蛋白的需求仍然未知。作为一种铁氧化酶，铜蓝蛋白通过铁转运蛋白促进铁输出，然而，由于铁转运蛋白降解，该功能在感染期间是不必要的。因此，铜蓝蛋白可能在感染期间具有替代功能。初步结果表明，铜蓝蛋白敲除小鼠对细菌病原体鼠伤寒沙门氏菌和金黄色葡萄球菌的全身感染高度敏感。此外，发现铜蓝蛋白敲除小鼠在受到 Toll 样受体 (TLR) 细菌配体攻击时，血清中促炎细胞因子水平降低，这凸显了铜蓝蛋白在 TLR 信号传导中的可能作用。在该提案中，将使用生化和遗传学方法来了解铜蓝蛋白对营养免疫的贡献。 AIM1 测试铁和铜对铜蓝蛋白缺失小鼠感染超敏反应的作用。 AIM 2 旨在了解铜蓝蛋白在巨噬细胞内 TLR 信号传导中的作用。 AIM 3 研究宿主免疫是否需要巨噬细胞或肝细胞表达铜蓝蛋白。