Role of C-type Lectin Receptors in Myeloid Plasticity in Neurocysticercosis

C型凝集素受体在神经囊尾蚴病骨髓可塑性中的作用

• 批准号: 8437115
• 负责人: JUDY M TEALE
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437115
• 关键词: Adrenal Cortex Hormones; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Biological Process; Brain; C Type Lectin Receptors; C-Type Lectins; Cell physiology; Cells; Central Nervous System Infections; Cephalic; Cestoda; Chronic; Clinical; Developing Countries; Disease; Environment; Epilepsy; Exhibits; Galactose; Goals; Helminths; Human; Hydrocephalus; Immigration; Immune; Immune Tolerance; Immune response; Immunologic Receptors; Immunosuppression; Immunosuppressive Agents; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intracranial Hypertension; Larva; Lead; Life; Location; Mediating; Mesocestoides; Molecular; Mus; Myelogenous; Myeloid Cells; Nervous System Trauma; Neuraxis; Neurocysticercosis; Neurologic; Organism; Parasites; Parasitic Diseases; Pathogenesis; Pathology; Patients; Pattern; Pattern recognition receptor; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Polysaccharides; Population; Property; Public Health; Role; Seizures; Severities; Specificity; Specimen; Staging; Suppressor-Effector T-Lymphocytes; Symptoms; T-Lymphocyte; Taenia solium; Testing; Therapeutic Intervention; Time; United States; Up-Regulation; Wild Type Mouse; Work; base; cytokine; human disease; immunoregulation; insight; macrophage; mannose receptor; mouse model; nervous system disorder; novel; novel therapeutic intervention; novel therapeutics; pathogen; receptor expression; response; sugar; trafficking; treatment strategy

DESCRIPTION (provided by applicant): Neurocysticercosis (NCC) is a common neurological disease in developing countries and the United States caused by the larva stages of the parasite Taenia solium. The pathogenesis and clinical manifestations vary with the location of the parasite within the brain and accompanying host immune response. Our long term goal has been to characterize and understand the host immune response and the pathology associated with NCC to establish better therapeutic interventions. Apart from analyses of brain specimens from NCC patients, we have developed a mouse model of NCC by intra-cranial infection with the related cestode, Mesocestoides corti. We have shown that the parasite releases glycans with distinct sugar specificities that are taken up by host cells in the CNS environment in both human and murine NCC. Of particular relevance, two C-type lectin receptors (CLRs) are highly up-regulated after parasite infection: mannose receptor (MRC1) and macrophage galactose C-type lectin (MGL1) which recognize sugars from parasite and host origin respectively. We hypothesize that recognition of parasite- released glycans via MRC1 leads to protective CNS responses. This is based on the observation that Mrc1-/- mice survive significantly longer and exhibit reduced CNS pathology that correlates with increased infiltration a novel population of myeloid cells with a suppressor phenotype. In contrast, Mgl1-/- mice show decreased survival and up-regulation of inflammatory cytokines. We further hypothesize that CLRs differentially modulate myeloid plasticity thus regulating the degree of inflammation vs. suppression in murine NCC. To test this, we will identify the effects of MRC1 and MGL1 in myeloid cell function during the early and late stages of murine NCC (Aim 1), and determine the mechanisms by which MRC1 modulate effector antigen specific T cell immune responses (Aim 2). Our proposed studies will provide the first detailed assessment of CLR expression and function in CNS parasite infections and present novel therapeutic strategies. PUBLIC HEALTH RELEVANCE: Neurocysticercosis is the most frequent parasitic disease affecting the central nervous system (CNS), and the clinical symptoms can be devastating and lifelong. The severity of the symptoms is associated with the intensity of the immunological response and involves innate immune receptors called C-type lectins, understudied molecules in the CNS. C-type lectins can induce immune suppression so understanding their function will likely result in new therapeutic strategies.

描述（由申请人提供）：神经囊虫病（NCC）是发展中国家和美国由寄生虫Taenia solium的幼虫阶段引起的常见神经系统疾病。发病机理和临床表现随寄生虫在大脑中的位置以及随附的宿主免疫反应而变化。我们的长期目标是表征和了解与NCC相关的宿主免疫反应以及与NCC相关的病理，以建立更好的治疗性干预措施。除了对NCC患者的脑标本进行分析外，我们还通过使用相关Cestode Mesocestoides Corti开发了NCC的小鼠模型。我们已经表明，寄生虫释放具有不同糖特异性的聚糖，这些糖特异性由人类和鼠NCC中的中枢神经系统环境中的宿主细胞占据。特别相关的是，两个C型凝集素受体（CLR）在寄生虫感染后高度上调：甘露糖受体（MRC1）和巨噬细胞半乳糖C型凝集素（MGL1）分别识别寄生虫和宿主起源的糖。我们假设对寄生虫通过MRC1释放的聚糖的认识导致保护性中枢神经系统的反应。这是基于以下观察结果：MRC1 - / - 小鼠的生存时间明显更长，并且表现出降低的CNS病理学，与浸润增加了抑制剂表型的新型髓样细胞群体相关。相反，MGL1 - / - 小鼠的生存率降低和炎症细胞因子的上调。我们进一步假设CLR差异调节髓样可塑性，从而调节鼠NCC中的炎症程度与抑制程度。为了测试这一点，我们将在鼠NCC的早期和晚期（AIM 1）确定MRC1和MGL1对髓样细胞功能的影响（AIM 1），并确定MRC1调节效应抗原特异性T细胞免疫反应的机制（AIM 2）。我们提出的研究将对中枢神经系统寄生虫感染中CLR表达和功能进行首次详细评估，并提出新颖的治疗策略。 公共卫生相关性：神经囊肿是影响中枢神经系统（CNS）的最常见的寄生疾病，临床症状可能是毁灭性的和终生的。症状的严重程度与免疫反应的强度有关，涉及固有的免疫受体，称为C型凝集素，中枢神经系统中的分子正在研究。 C型凝集素可以诱导免疫抑制，因此了解其功能可能会导致新的治疗策略。