Mannose Binding Lectin in Neuroinflammation and NeuroAIDS

甘露糖结合凝集素在神经炎症和神经艾滋病中的作用

基本信息

批准号：
8393063
负责人：
KUMUD K SINGH
金额：
$ 34.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8393063
关键词：
AIDS neuropathy Adult Affect Alleles Alzheimer&apos s Disease Amyloid Antigen-Antibody Complex Apoptosis Apoptotic Astrocytes Autoantigens Autoimmunity Bacteria Binding Biological Markers Brain Cells Central Nervous System Infections Cessation of life Characteristics Child Code Complement Complement Activation Complex DNA Deposition Development Disease Disease Progression Employee Strikes Enzyme-Linked Immunosorbent Assay Failure Fluorescence Microscopy Genes Genotype HIV HIV Infections HIV-1 Human Immune Immune response Impairment Individual Infection Inflammatory Inflammatory Response Pathway Leukocytes Link Mannose Mannose Binding Lectin Mannose-Binding Lectins Measures Mediating National NeuroAids Tissue Consortium Natural Immunity Neuraxis Neurocognitive Neuronal Injury Neurons Neuropathogenesis Outcome Phagocytosis Phase Plasma Polysaccharides Predisposition Proteins RNA Recombinants Research Risk Role Sampling Serine Protease Site Surface Techniques Testing Therapeutic Tissues Validation Variant Viral Viral Antigens Viral Proteins Virus Virus Diseases antiretroviral therapy brain tissue complement pathway cytokine genetic variant macrophage mannose-binding protein-associated serine proteases migration neurobehavioral neuroinflammation neurotoxicity neutrophil novel pathogen protein complex public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Human immunodeficiency virus-1 (HIV-1) is detected early in central nervous system (CNS) and causes neuroinflammation leading to the initiation and expansion of neuronal injury and death. In USA alone, 40% of about 1 million HIV-1 infected individuals are likely to acquire HIV-1 related CNS impairment. The innate immune mechanisms underlying HIV-1 neuropathogenesis and CNS impairment have been understudied. Mannose binding lectin (MBL), coded by MBL2 gene, is an active phase protein that mounts innate immune response against risk of infections by recognizing mannose residues present on the surface of pathogens (e.g. viruses, bacteria) and initiating the complement pathway by activating MBL- associated serine proteases (MASPs). MBL binds to high mannose N-linked glycan residues of HIV-1 gp41/120 and elicits cytokine responses and macrophage mediated HIV-1 opsonization. Thus, lower MBL expression or function can result in neuroinflammation and anomalous accumulation of viral proteins and immune complexes in brain leading to neurotoxicity and neurocognitive impairment. Recently, in about 1000 HIV-1 infected children we showed that the presence of MBL2 genetic variants resulting in expression of non-functional MBL was associated with more rapid progression of CNS impairment. Although effects of MBL2 variants on susceptibility of HIV-1 and disease progression are known; their association with the progression of CNS impairment is a new finding. The proposed research seeks to extend this new finding by studying the association of MBL expression and function to the susceptibility and progression of HIV-1 related neuroinflammation and CNS impairment. Our overarching hypothesis is that lower expression and altered function of MBL impairs MBL-mediated complement activation, related cytokine responses; scavenger opsonization function and leads to increased susceptibility to HIV-1 infection and neuroinflammation, accumulation of viral/complement proteins or autoantigens in brain, and eventually neurocognitive impairment. Additionally, variant MBL2/MASP-2 alleles alter expression and function of MBL in CNS. For these studies, we will determine the MBL, MASPs and complement protein levels in paired CSF/plasma from HIV infected impaired/unimpaired adults (N=2385) from HIV Neurobehavioral Research Center (HNRC, UCSD); and post-mortem brain tissues (N=45) from National NeuroAIDS Tissue Consortium (NNTC, Rockville, MD) using highly sensitive multiplex ELISAs, innate immune response microarray analyses during HIV infection, quantitative PCR validation, genotyping, immunohistostaining and fluorescence microscopy techniques. These studies will help to understand the novel role of MBL and related innate immunity complement biomarkers in HIV related neuroinflammation and neurocognitive impairment; and might suggest avenues for development of effective therapeutics such as recombinant human MBL.

描述（由申请人提供）：在中枢神经系统（CNS）早期检测到人类免疫缺陷病毒-1（HIV-1），并导致神经炎症导致神经元损伤和死亡的启动和扩展。仅在美国，约有100万HIV-1感染的人中有40％可能会获得与HIV-1相关的CNS损害。 HIV-1神经病发生和中枢神经系统损害的先天免疫机制已被研究。由MBL2基因编码的甘露糖结合凝集素（MBL）是一种活性相蛋白，通过识别病原体表面上存在的甘露糖残基（例如病毒，细菌）并通过激活MBL相关的塞氨酸蛋白蛋白酶（Masps）来启动补体途径，通过识别出存在于病原体表面上的甘露糖残基来安装先天性免疫反应。 MBL与HIV-1 GP41/120的高甘露糖N-连接的聚糖残基结合，并引起细胞因子反应和巨噬细胞介导的HIV-1调子化。因此，较低的MBL表达或功能会导致病毒蛋白和免疫复合物在大脑中的神经炎症和异常积累，从而导致神经毒性和神经认知障碍。最近，在大约1000名HIV-1感染儿童中，我们表明，导致非功能MBL表达的MBL2遗传变异的存在与CNS损伤的更快进展有关。尽管已知MBL2变体对HIV-1和疾病进展的易感性的影响。他们与中枢神经系统障碍的进展的关联是一个新发现。拟议的研究试图通过研究MBL表达和功能与HIV-1相关神经炎症和CNS损害的易感性和进展的关联来扩展这一新发现。我们的总体假设是，MBL的较低表达和变化的功能会损害MBL介导的补体激活，相关的细胞因子反应。清除式调整功能，并导致对HIV-1感染和神经炎症的敏感性增加，病毒/补体蛋白质或自身抗原在大脑中的积累以及最终的神经认知障碍。另外，变体MBL2/MASP-2等位基因改变了CNS中MBL的表达和功能。在这些研究中，我们将确定来自HIV感染受损/未受损的成年人（N = 2385）的MBL，MASP和补体蛋白水平（HNRC，UCSD）；来自国家神经辅助组织（NNTC，Rockville，MD）的尸体后脑组织（n = 45），使用高度敏感的多重ELISA，HIV感染期间的先天免疫反应微阵列分析，定量PCR验证，基因型型，免疫疗法和荧光显微镜副本。这些研究将有助于了解MBL和相关的先天免疫的新作用，并补充与HIV相关的神经炎症和神经认知障碍中的生物标志物。并可能暗示开发有效治疗学的途径，例如重组人MBL。