Alarmin-mediated control of CNS infection

警报素介导的中枢神经系统感染控制

• 批准号: 10523982
• 负责人: TAJIE H. HARRIS
• 金额: $ 5.16万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523982
• 关键词: Address; Adult; Affect; Alzheimer' s Disease; Antiparasitic Agents; Area; Astrocytes; Blood Vessels; Brain; Brain region; CCL2 gene; Cell Adhesion Molecules; Cell Death; Cells; Central Nervous System Infections; Chemotaxis; Chronic; Cyst; Data; Defect; Disease Progression; Endothelial Cells; Endothelium; Extravasation; Immune; Immune response; Immune system; Immunity; Infection; Infection Control; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Interferon Type II; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 alpha; Interleukin-1 beta; Lead; Link; Location; Mediating; Microglia; Mus; Myeloid Cells; Nerve Degeneration; Neuraxis; Neuroglia; Oligodendroglia; Parasite Control; Parasites; Parasitic infection; Pathway interactions; Production; Proteins; Publications; Reaction; STAT1 gene; Signal Transduction; Signaling Molecule; Single Nucleotide Polymorphism; Site; Source; System; T-Lymphocyte; Testing; Tissues; Toxoplasma gondii; Toxoplasmosis; brain endothelial cell; cell injury; cell type; chemokine; chronic infection; gray matter; interest; macrophage; mild cognitive impairment; mind control; monocyte; multiphoton microscopy; neuroinflammation; pathogen; prevent; receptor; recruit; response; therapeutic development; trafficking; transcriptome sequencing

PROJECT SUMMARY Infections can cause irreversible damage to the brain. In this proposal, we aim to understand how the immune system is mobilized to specific regions of the brain to eliminate pathogens. The parasite Toxoplasma gondii causes a chronic brain infection where the parasite persists in an intracellular cyst form. When cysts reactivate, vigorous immune responses occur in these regions that limit parasite replication. Our preliminary data and a recent publication highlight the necessity of recruiting inflammatory monocytes to the brain to control infection. The inflammatory networks that recruit monocyte-derived macrophages to the brain and specifically to regions of cyst reactivate have not been identified and are the focus of this proposal. In preliminary studies, we find that two host alarmins (molecules that are released from damaged and dying cells), IL-33 and IL-1α, are necessary to bring myeloid cells into the brain and control parasite burden. In this proposal, we will address the central hypothesis that IL-33 and IL-1α act through non-redundant inflammatory pathways to drive the recruitment of monocytes to the brain to control parasite replication. Specifically, in Aim 1 we will examine the key IL-33R- expressing cells in the CNS, which we hypothesize make the chemokine, CCL2, that drives monocyte chemotaxis. In Aim 2, we propose to investigate the key cells that release and respond to IL-1α during infection. We hypothesize that IL-1α acts on the endothelium to induce adhesion molecule expression necessary for monocyte trafficking into the brain. In Aim 3 we will examine how the inability to sense both alarmins affects the control of infection. Overall, these studies will define how tissue damage drives protective immune responses in the brain. The inflammatory pathways triggered by alarmins are of great interest in the context of multiple neuroinflammatory conditions, including Alzheimer’s disease, where SNPs in the receptor required for both IL- 1α and IL-33 signaling, IL-1RAP have been linked to disease progression. The results from these studies may lead to the development of therapeutics that promote or prevent focal immune responses in the brain.

项目摘要 感染会对大脑造成不可逆转的损伤。在这项提案中，我们的目标是了解免疫系统如何 系统被动员到大脑的特定区域以消除病原体。寄生虫弓形虫 导致慢性脑部感染，寄生虫以胞内囊肿的形式存在。当囊肿重新激活时， 在这些区域中发生强烈的免疫应答，限制寄生虫复制。我们的初步数据和 最近的出版物强调了将炎性单核细胞募集到脑中以控制感染的必要性。 炎症网络将单核细胞衍生的巨噬细胞募集到大脑，特别是区域 囊肿再激活的可能性尚未确定，这是本提案的重点。初步研究发现， 需要两种宿主alarmins（从受损和垂死细胞释放的分子），IL-33和IL-1α， 将骨髓细胞带入大脑并控制寄生虫负担。在本建议中，我们将讨论中央 假设IL-33和IL-1α通过非冗余的炎症途径作用， 单核细胞到大脑来控制寄生虫的复制。具体而言，在目标1中，我们将研究关键的IL-33 R-1。 在中枢神经系统中表达细胞，我们假设它产生趋化因子CCL 2，驱动单核细胞 趋化性在目的2中，我们提出研究在感染过程中释放和响应IL-1α的关键细胞。 我们假设IL-1α作用于内皮细胞，诱导粘附分子表达， 单核细胞进入大脑在目标3中，我们将研究无法感知这两种警报如何影响 控制感染。总的来说，这些研究将确定组织损伤如何驱动保护性免疫反应， 大脑由alarmin触发的炎症通路在多种炎症背景下引起了极大的兴趣。 神经炎性疾病，包括阿尔茨海默氏病，其中受体中的SNP需要IL- 1α和IL-33信号传导，IL-1 RAP与疾病进展有关。这些研究的结果可能 导致促进或预防脑中局部免疫反应的治疗方法的发展。