Theiler?s virus as a potential cause of Vilyuisk encephalitis

描述(由申请人提供)：这份R21探索性建议的目标是确定被称为Vilyuisk人脑炎病毒(VHEV)的V-1分离株是否是Vilyuisk脑脊髓炎(VE)的病原体，它可能代表Vilyuisk人脑炎病毒的一个单独分支。虽然VE的病毒原因尚不清楚，但有令人信服的证据将VHEV与VE联系起来。VE已经从沿Vilyui河中游的地方性区域扩展到Lena-Aldan河谷中人口更多的新地理区域，那里是俄罗斯西伯利亚萨卡共和国首府雅库茨克所在的地方。由于航空旅行自由度的增加而导致的全球化可能会导致VE进一步蔓延到世界其他区域。最近在北美和其他四个大洲的不同地理位置的呼吸道和腹泻儿童中发现了名为Saffold Virus(SafV)的病毒，这表明这些病毒是全球性的，通常感染儿童和可能的成年人。轮状病毒的出现是我们对VE病因重新产生兴趣的催化剂，因为轮状病毒导致人类中枢神经系统(CNS)疾病是值得称赞的。事实上，PI刚刚从欧洲儿童脑炎病例中了解到SAFV分离株。因此，推测ILO病毒代表了一组新兴的人类病毒，导致中枢神经系统感染，包括VE(假设)，这是很有趣的。(1)为了研究VHEV与VE临床疾病之间的联系，我们将测定VE患者和对照组VHEV的血清效价和血清：脑脊液(CSF)中和抗体的比率，VE脑脊液(CSF)对VHEV的寡克隆条带(OCB)反应性，以及从VE脑脊液提取的总RNA中是否能扩增出一个320碱基的含有高度可变的VP2泡芙(EF)结构的心肌病毒扩增片段。(2)在VHEV不能与VE相连的情况下，从VE脑脊液中提取的总RNA中反转录的cDNA将与寡核苷酸病毒微阵列(GreenChipsPm)杂交，并用于高通量测序，通过减去人类转录组来检测特定脊椎动物病毒家族的外源(非人类)序列。公共卫生相关性：这是一项探索性建议，旨在确定发生在俄罗斯东北部(西伯利亚)萨卡共和国的一种慢性中枢神经系统疾病的病毒病因。这种疾病名为Vilyuisk脑脊髓炎，与多发性硬化症有一些相似之处，似乎是由人类泰勒病毒引起的。小鼠的对应物是泰勒氏小鼠脑脊髓炎病毒，它为多发性硬化症提供了一个高度相关的实验动物模型。

DESCRIPTION (provided by applicant): The goal of this R21 exploratory proposal is to determine whether the V-1 isolate, termed Vilyuisk human encephalitis virus (VHEV), which may represent a separate clade of theilovirus, is the causative agent of Vilyuisk encephalomyelitis (VE). Although the viral cause of VE remains unknown compelling evidence links VHEV to VE. VE has spread 400 km from the area of endemicity along the middle reaches of the Vilyui River to a new more populous geographic area in the Lena-Aldan river valleys where Yakutsk, the capital of the Sahka Republic in Siberia (Russia), is located. Globalization due to increased freedom of air travel could result in further spread of VE to other regions of the world. Recent identification of theiloviruses designated Saffold viruses (SafV) in children with respiratory and diarrheal diseases from separate geographic locations in North America and four other continents indicate that theiloviruses are global in distribution and commonly infect children and possibly adults. The emergence of theiloviruses is the catalyst for our renewed interest in the cause of VE since it is creditable that theiloviruses cause human central nervous system (CNS) diseases. In fact, the PI has just learned of SafV isolations from cases of encephalitis in children in Europe. Therefore, it is intriguing to speculate theiloviruses represent an emerging group of human viruses that cause central nervous system CNS infections, including VE (hypothesis). Two specific aims are proposed: (1) To investigate a link between VHEV and the clinical disease of VE, we will determine serum titers and serum:CSF ratios of ELISA and neutralizing antibodies to VHEV in VE cases and controls, VE cerebrospinal fluid (CSF) oligoclonal band (OCB) reactivity to VHEV, and whether a 320- bp Cardiovirus amplicon that includes the highly variable VP2 puff (EF) structures can be amplified from total RNA extracted from VE CSF. (2) In the event that VHEV cannot be linked to VE, reverse transcribed cDNA from total RNA extracted from VE CSF will be hybridized to oligonucleotide viral microarrays (GreenChipsPm) and also used for high-throughput sequencing to detect foreign (non-human) sequences of a specific vertebrate virus family by subtraction of the human transcriptisome. PUBLIC HEALTH RELEVANCE: This is an exploratory proposal to determine the viral cause of a chronic central nervous system disease that occurs in the Sahka Republic in far northeastern Russia (Siberia). This disease, Vilyuisk encephalomyelitis, has some similarities to multiple sclerosis and appears to be caused by a human Theilovirus. The murine counterpart, Theiler's murine encephalomyelitis virus, provides a highly relevant experimental animal model for multiple sclerosis.