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

基本信息

批准号：
8858696
负责人：
Astrid E Cardona
金额：
$ 32.16万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8858696
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

项目摘要

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.

描述（由申请人提供）：神经囊尾蚴病（NCC）是发展中国家和美国的一种常见神经系统疾病，由寄生虫猪带绦虫的幼虫阶段引起。发病机制和临床表现因寄生虫在大脑内的位置和伴随的宿主免疫反应而异。我们的长期目标是表征和了解宿主免疫反应以及与 NCC 相关的病理学，以建立更好的治疗干预措施。除了对 NCC 患者的脑标本进行分析外，我们还通过相关绦虫 Mesocetoides corti 的颅内感染建立了 NCC 小鼠模型。我们已经证明，寄生虫会释放具有独特糖特异性的聚糖，这些聚糖被人类和小鼠 NCC 中枢神经系统环境中的宿主细胞吸收。特别重要的是，寄生虫感染后，两种 C 型凝集素受体 (CLR) 高度上调：甘露糖受体 (MRC1) 和巨噬细胞半乳糖 C 型凝集素 (MGL1)，它们分别识别寄生虫和宿主来源的糖。我们假设通过 MRC1 识别寄生虫释放的聚糖会导致保护性中枢神经系统反应。这是基于以下观察结果：Mrc1-/- 小鼠的存活时间显着延长，并表现出中枢神经系统病理减少，这与具有抑制表型的新型骨髓细胞群的浸润增加相关。相比之下，Mgl1-/- 小鼠的存活率下降，炎症细胞因子上调。我们进一步假设 CLR 差异调节骨髓可塑性，从而调节小鼠 NCC 中炎症与抑制的程度。为了测试这一点，我们将确定 MRC1 和 MGL1 在小鼠 NCC 早期和晚期阶段对骨髓细胞功能的影响（目标 1），并确定 MRC1 调节效应抗原特异性 T 细胞免疫应答的机制（目标 2）。我们提出的研究将首次详细评估中枢神经系统寄生虫感染中的 CLR 表达和功能，并提出新的治疗策略。