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铜毒酶Ceruroplasmin通过调节细菌感染的营养免疫学调节营养免疫学的机制。迫切需要了解营养体稳态的机制，以开发更有效的治疗方法和疗法。营养免疫学描述了在微生物感染过程中改变宿主金属离子稳态的机制。营养免疫学的一个重要方面是通过低铁血症（低血浆铁水平）从细菌病原体中预扣铁。低铁血症受辣椒蛋白的调节，肝素肝素通过诱导铁出口剂的降解，肝细胞，肠细胞和巨噬细胞的降解来限制铁出口到血浆中。营养免疫的另一种机制涉及高收血症（高血浆铜水平）。该过程是通过增加的甲状腺素分泌的肝素分泌，这是一种含铜含有铁氧化酶的铜，在血浆中含有大多数铜。人们认为铜可以通过先天免疫系统的巨噬细胞维持细菌病原体的杀伤，但是，Ceruloprasmin在此过程中的作用尚不清楚。尽管60多年前它鉴定为急性期蛋白质，但感染过程中ceruloprasin的需求仍然未知。作为铁氧化酶，Ceruloprasin促进了铁素的铁出口，但是，由于铁托蛋白降解，该功能在感染过程中是不必要的。这是ceruroplasmin在感染过程中可能具有替代功能。初步结果表明，细菌病原体鼠伤寒沙门氏菌和金黄色葡萄球菌的细菌病原体高度易受全身感染。此外，当用细菌配体挑战Tollike接收器（TLRS）时，发现Ceruroplasmin基因敲除小鼠暴露于血清促炎细胞因子的降低水平，突显了ceruloprasmin在TLR信号中的可能作用。在此提案中，将使用生化方法和遗传方法来了解ceruloprasmin对营养免疫的贡献。 AIM1测试了铁和铜对谷链蛋白酶无小鼠的超敏反应的作用。 AIM 2试图了解Ceruloprasin在巨噬细胞中TLR信号传导中的作用。 AIM 3研究宿主免疫需要巨噬细胞或肝细胞表达。