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首页> 外文学位 >Central nervous system infection of the human herpesvirus-6 and mechanisms of neuroinflammation mediated by engagement of the CD46 virus receptor.
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Central nervous system infection of the human herpesvirus-6 and mechanisms of neuroinflammation mediated by engagement of the CD46 virus receptor.

机译：人疱疹病毒6的中枢神经系统感染和CD46病毒受体参与介导的神经炎症机制。

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摘要

Infectious etiology in multiple sclerosis (MS) has previously been raised. Despite many studies demonstrating associations with multiple pathogens, no MS-specific agent has been identified. Thus, it has been hypothesized that in genetically susceptible individuals, infectious agents could act as triggers in eliciting aberrant immune responses directed against the central nervous system (CNS). The human herpesvirus-6 (HHV-6), a neurotropic virus, is a frequently implicated candidate pathogens in MS. To better understand the role of HHV-6 in the pathogenesis of neurologic diseases, we compared detection of cell-free HHV-6 DNA and antibody reactivity in the cerebrospinal fluid (CSF) specimens of various neurologic cohorts. Differences in levels of HHV-6 antibody and HHV-6 DNA expression in various neurologic cohorts were demonstrated. To understand the specific mechanisms that allow HHV-6 infection of the CNS, whether HHV-6 could infect primary human astrocyte cultures in vitro and explored the potential of this virus to enter the CNS using the olfactory pathway by infecting a specialized group of glial cells located in the nasal cavity known as olfactory ensheathing glial cells (OEGCs) was investigated. The findings suggest ability of HHV-6 to enter and establish life-long residency in the brain through infection of glial cells such as OEGCs and CNS astrocytes. Furthermore, we hypothesize that immune surveillance may actively be involved in preventing CNS activation of HHV-6 in healthy individuals. Impairment in immune control, however, could lead to viral reactivations. Using paired CSF and sera specimen of a small cohort patients who were treated with natalizumab, a monoclonal antibody against the alpha-4-beta-integrin molecule used in treatment of MS that blocks immune cell trafficking to the brain, we demonstrated evidence of HHV-6 reactivation by PCR detection, suggesting reduction in circulating immune cells is associated with viral reactivation within the CNS. Moreover, binding of the HHV-6 with the CD46 virus receptor/T cell co-stimulatory molecule was also investigated as a possible mechanism contributing to a by-stander pro-inflammatory reaction associated with neural tissue damage in genetically susceptible individuals.
机译：先前已经提出了多发性硬化症（MS）中的传染病因。尽管有许多研究表明与多种病原体相关，但尚未鉴定出MS特异性药物。因此，已经假设在遗传易感的个体中，传染原可以充当引发针对中枢神经系统（CNS）的异常免疫反应的触发因素。人疱疹病毒6（HHV-6）是一种向神经性病毒，是MS中经常涉及的候选病原体。为了更好地了解HHV-6在神经系统疾病的发病机理中的作用，我们比较了各种神经系统人群的脑脊髓液（CSF）标本中无细胞HHV-6 DNA的检测和抗体反应性。证明了在各种神经病学队列中HHV-6抗体和HHV-6 DNA表达水平的差异。为了了解允许HHV-6感染中枢神经系统的具体机制，HHV-6是否可以在体外感染原代人星形胶质细胞培养，并通过感染特殊的神经胶质细胞组来探索该病毒利用嗅觉途径进入中枢神经系统的潜力。位于鼻腔的嗅鞘神经胶质细胞（OEGCs）被调查。这些发现表明，HHV-6能够通过感染OEGC和CNS星形胶质细胞等神经胶质细胞而进入并在大脑中建立终生驻留能力。此外，我们假设免疫监视可能积极参与预防健康个体中枢神经系统激活HHV-6。但是，免疫控制功能受损可能导致病毒重新激活。使用成对的小脑部患者的脑脊液和血清标本，接受那他珠单抗治疗，那他单抗是用于治疗MS的α-4-β-整联蛋白分子的单克隆抗体，可阻断免疫细胞向大脑的运输，我们证明了HHV- 6通过PCR检测重新激活，提示循环免疫细胞减少与CNS内的病毒重新激活有关。此外，还研究了HHV-6与CD46病毒受体/ T细胞共刺激分子的结合，这可能是导致遗传易感个体中与神经组织损伤相关的旁观者促炎反应的可能机制。

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  • 作者

    Yao, Karen J.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Biology Cell.;Health Sciences Immunology.;Biology Virology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 264 p.
  • 总页数 264
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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