Overcome of virus-induced neurological disorders: analysis of neurological mechanisms inducing viral persistent infection in the central nervous system

克服病毒引起的神经系统疾病：病毒引起中枢神经系统持续感染的神经机制分析

• 批准号: 15390148
• 负责人: TOMONAGA Keizo
• 金额: $ 9.73万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390148/
• 关键词: Borna disease virus; Central nervous system; Persistent Infection; RAGE; Viral neuropathogenesis; CNS immunity; 感染病態

Borna disease virus (BDV) belongs to the Bornaviridae family, within the nonsegmented negative-strand RNA virus, Mononegavirales, which is characterized by highly neurotropic, noncytopathic replication, and persistent infection. Although previous studies using rodent models indicated that modulation of the immune response, such as BDV-specific Thl tolerance, could contribute to the induction of persistence in the brain, the mechanisms by which CNS viruses efficiently control immune response have not been yet fully elucidated. In this study, to understand the strategy that neurotropic virus evades host response, we investigated the role of the receptor for advanced lycation end products (RAGE), which is involved in the immune system's response pathways, in BDV-infected brains. Newborn or 4-weeks old Lewis rats were intracranially inoculated with BDV. To examine the role of RAGE in CNS virus infection, expression level of RAGE and its ligands was traced with the viral propagation. We found that RAGE expression gradually decreased in BDV-infected brain in correlation with viral propagation despite the upregulation of potent RAGE ligands, such as HMGB1 and S100B. Interestingly, BDV persistent brains displayed no reactivation of the RAGE expression and reduced reaction to the induction of inflammatory response even by the injection of several antigens. In experimental autoimmune encephalomyelitis, persistently infected rats induced only mild inflammation in the cerebellum. We demonstrated the downregulation of RAGE expression in the brain persistently infected with BDV. Resent reports have revealed that RAGE is involved in the host immune reaction and its expression might be required for the perpetuation of the innate immune response. Our observations suggested that BDV infection could escape form the inflammatory response by the regulation of RAGE expression in the brain, leading to the development of persistent infection.

博尔纳病病毒（BDV）属于博尔纳病毒科，属于非节段负链RNA病毒单链病毒，其特点是高度嗜神经性、非细胞病变性复制和持续感染。尽管先前使用啮齿动物模型的研究表明，免疫反应的调节，如bdv特异性Thl耐受性，可能有助于在大脑中诱导持久性，但中枢神经系统病毒有效控制免疫反应的机制尚未完全阐明。在这项研究中，为了了解嗜神经病毒逃避宿主反应的策略，我们研究了bdv感染大脑中参与免疫系统反应途径的晚期lycation终产物受体（RAGE）的作用。新生或4周龄Lewis大鼠颅内接种BDV。为了研究RAGE在CNS病毒感染中的作用，我们追踪了RAGE及其配体在病毒传播过程中的表达水平。我们发现，尽管有效的RAGE配体（如HMGB1和S100B）上调，但在bdv感染的大脑中，RAGE表达逐渐下降，与病毒传播相关。有趣的是，即使注射了几种抗原，BDV持续存在的大脑也没有表现出RAGE表达的再激活和对炎症反应的诱导反应的减少。在实验性自身免疫性脑脊髓炎中，持续感染的大鼠仅在小脑中引起轻度炎症。我们证实了RAGE在持续感染BDV的大脑中表达下调。最近的报道显示，RAGE参与宿主免疫反应，其表达可能是先天免疫反应的延续所必需的。我们的观察结果表明，BDV感染可以通过调节大脑中RAGE的表达来逃避炎症反应，从而导致持续感染的发展。

项目成果

Prevalence of Borna disease virus antibodies in health Japanese black cattle in Kyushu.

九州健康黑牛博尔纳病病毒抗体的流行情况。

• 发表时间: 2006
• 期刊: Journal of Veterinary Medical Science 68
• 作者: Kazushige Midorikawa;Kazuhisa Ouhara;Hitoshi Komatsuzawa;Toshihisa Kawai;Sakuo Yamada;Tamaki Fujiwara;Kenshi Yamazaki;Koji Sayama;Martin A.Taubman;Hidemi Kurihara;Koji Hashimoto;Motoyuki Sugai;Motoyuki Sugai;Kazushige Midorikawa et al.;Yanai et al.;Watanabe et al.
• 通讯作者: Watanabe et al.

Tomonaga et al.: "Virus-induced neurobehavioral disorders : mechanisms and implications"Trends in Molecular Medicine. 10. 71-77 (2004)

Tomonaga 等人：“病毒引起的神经行为障碍：机制和影响”分子医学趋势。

Virus-induced neurobehavioral disorders: mechanisms and implications.

• DOI: 10.1016/j.molmed.2003.12.001
• 发表时间: 2004-02
• 期刊: Trends in molecular medicine
• 影响因子: 13.6
• 作者: Tomonaga K

Development of a novel Borna disease virus reverse genetics system using RNA polymerase II promoter and SV40 nuclear import signal

• DOI: 10.1016/j.micinf.2006.01.010
• 发表时间: 2006-05-01
• 期刊: MICROBES AND INFECTION
• 影响因子: 5.8
• 作者: Yanai, Hideyuki;Hayashi, Yohei;Tomonaga, Keizo
• 通讯作者: Tomonaga, Keizo

Persistent Borna Disease Virus Infection Confers Instability of HSP70 mRNA in Glial Cells during Heat Stress

• DOI: 10.1128/jvi.79.4.2033-2041.2005
• 发表时间: 2005-02
• 期刊: Journal of Virology
• 影响因子: 5.4
• 作者: M. Yamashita;W. Kamitani;H. Yanai;Naohiro Ohtaki;Yohei Watanabe;Byeong-Jae Lee;S. Tsuji;K. Ikuta;K. Tomonaga