H5N1 Influenza Virus as a Novel Etiological Agent in Parkinsons Disease

H5N1 流感病毒作为帕金森病的新病原体

• 批准号: 7825434
• 负责人: RICHARD J SMEYNE
• 金额: $ 20.79万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7825434
• 关键词: Affect; Alzheimer' s Disease; Animal Model; Animals; Area; Asia; Astrocytes; Avian Influenza; Birds; Brain; Cell Count; Cells; Cessation of life; Characteristics; Corpus striatum structure; Data; Detection; Disease; Disease Outbreaks; Dopamine; Encephalitis; Encephalitis Lethargica; Enteric Nervous System; Epithelial Cells; Etiology; Exposure to; Future; Gene Mutation; Human; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Intranasal Administration; Lead; Life; Link; Maps; Microglia; Modeling; Mus; Mutate; Nervous System Trauma; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurotropism; New York; Parkinson Disease; Parkinsonian Disorders; Peripheral; Population; Reaction; Reporting; Risk; Site; System; Time; Toxic effect; Toxin; Uncertainty; Upper Respiratory Infections; Virulence; Virus; Virus Diseases; Writing; base; cytokine; exposed human population; influenza virus strain; influenzavirus; killings; meetings; motor disorder; neurotropic; novel; pandemic disease; pandemic influenza; public health relevance; transmission process; web site

DESCRIPTION (provided by applicant): The etiology of Parkinson's disease is multivariate, ranging from identified genetic mutations to strict environmental causation. Parkinson's disease can also occur following exposure to viruses, including the influenza virus. Most influenza infection in humans result in upper respiratory tract infection, but occasionally the brain is affected. At this time, there is considerable threat of a worldwide pandemic from the H5N1 strain of influenza virus, the so called "bird-flu". Previously, the great influenza pandemic of 1918, caused by an H1N1 influenza virus, affected 25-30% of the world's population, killing more than 40 million people. In the surviving population, the pandemic was linked to an outbreak of encephalitis lethargica (Von Economo's disease) followed by a spike in post-encephalic Parkinson's disease. Our preliminary results show that the H5N1 virus is neurotropic and can infect a variety of CNS and PNS areas. However, it is not known if the H5N1 virus can induce specific neurological damage. Since the H5N1 virus has the potential to mutate and start human-to-human transmission (likely leading to worldwide pandemic flu), it is critical to examine-in a mammalian species-if this virus has the ability to contribute to postencephalic neurodegenerative disease with particular emphasis on induced parkinsonism. In this application we propose three specific aims. Specific Aim 1 will determine the time-course for H5N1 influenza virus infection in the central, peripheral and enteric nervous systems of mice after intranasal inoculation. Here we will use immunohistochemical detection of H5N1 virus to map the presence of H5N1 at 1, 3, 7, 10, 21, 28, 60 and 90 days following intranasal administration of H5N1. We will also examine what cells get infected by H5N1 (neurons, astrocytes, microglia, epithelial cells) as well as determine how the virus enters the nervous system. Specific aim 2 will empirically determine if H5N1 influenza virus infection results in a loss of SNpc neurons or depletion of dopamine in its target the striatum as well as if the presence of H5N1 induces an immunological reaction, and Specific Aim 3 will determine if prior CNS infection with H5N1 influenza virus increases the sensitivity to the parkinsonian toxin MPTP. PUBLIC HEALTH RELEVANCE: There are great uncertainties about the timing, virulence, and general scope of a future human influenza pandemic. However, H5N1 has recently demonstrated considerable pandemic potential. There are 3 characteristics that a pandemic influenza strain must have: 1) it must be a new strain of influenza virus never seen in human populations before 2) it must be able to replicate and cause diseases in humans 3) it must transmit efficiently from human to human. H5N1 already meets the first 2 characteristics. Additionally, it is now spreading worldwide through avian populations, possibly becoming endemic in many regions and thereby increasing the risk of human exposure. If an H5N1 human pandemic were to occur, the impact on human populations would be enormous. Estimates of projected casualties vary tremendously, from 2 to 360 million worldwide, depending on assumptions about the lethality of the virus which can vary greatly as the virus adapts to humans (WHO website). However, what is clear is that a significant proportion of the world's population would become infected. Based upon reports of H5N1 neurotropism, including our preliminary studies (see below), an Op-Ed in the New York Times by of Oliver Sacks become particularly prophetic 38. Here, he writes " ...we would do well to reawaken ourselves to what may be a formidable threat not only to human lives, but also to the human brain in those who will survive an H5N1 influenza infection".

描述（由申请人提供）：帕金森氏病的病因是多元的，从鉴定的遗传突变到严格的环境因果关系。帕金森氏病在接触病毒后也可能发生，包括流感病毒。人类中大多数流感感染会导致上呼吸道感染，但有时会影响大脑。目前，H5N1流感病毒菌株（所谓的“ Bird-Flu”）受到全世界大流行的威胁。以前，由H1N1流感病毒引起的1918年的伟大流感大流行，影响了世界人口的25-30％，造成超过4000万人的造成。在幸存的人群中，大流行与脑炎脑炎（von cancemo氏病）的爆发有关，随后是脑插后帕金森氏病的激增。我们的初步结果表明，H5N1病毒是神经性的，可以感染各种CNS和PNS区域。但是，尚不清楚H5N1病毒是否会诱导特定的神经系统损害。由于H5N1病毒有可能突变和开始人类到人类传播（可能导致全球流感流感），因此对哺乳动物物种进行检查至关重要 - 如果该病毒有能力有助于后脑神经退行性疾病，并特别强调诱导的parkinsonismism。在此应用程序中，我们提出了三个具体目标。特定的目标1将确定鼻内接种后小鼠中心，周围和肠神经系统中H5N1流感病毒感染的时间顺序。在这里，我们将使用H5N1病毒的免疫组织化学检测来绘制H5N1在鼻内施用H5N1后1、3、7、10、21、28、60和90天的存在。我们还将检查哪些细胞被H5N1（神经元，星形胶质细胞，小胶质细胞，上皮细胞）感染，并确定病毒如何进入神经系统。 Specific aim 2 will empirically determine if H5N1 influenza virus infection results in a loss of SNpc neurons or depletion of dopamine in its target the striatum as well as if the presence of H5N1 induces an immunological reaction, and Specific Aim 3 will determine if prior CNS infection with H5N1 influenza virus increases the sensitivity to the parkinsonian toxin MPTP.公共卫生相关性：关于未来人类流行性流行病的时机，毒力和一般范围的极大不确定性。但是，H5N1最近表现出了巨大的大流行潜力。大流行性流感菌株必须具有3个特征：1）它必须是人类中从未见过的新型流感病毒菌株2）2）必须能够复制并引起人类疾病3）必须有效地从人类传播到人类。 H5N1已经符合前两个特征。此外，它现在正在通过鸟类种群在全球范围内传播，这可能在许多地区成为地方病，从而增加了人类暴露的风险。如果发生H5N1人类大流行，对人类人群的影响将是巨大的。预计伤亡人数的估计在全球范围内的2到3.6亿，这取决于对病毒的致命性的假设，随着病毒适应人类（WHO网站），这种病毒的致命性差异很大。但是，很明显，世界人口中很大一部分将被感染。基于H5N1神经性的报道，包括我们的初步研究（见下文），《纽约时报》在《纽约时报》上由奥利弗·萨克斯（Oliver Sacks）撰写的一本专栏文章特别是预言38。在这里，他写道：“ ...我们会很好地唤醒自己，以使自己对人类的生命不仅对人类的生命，而且对那些会影响H5n的人类脑中的人类大脑，还可以使H5n的生存感染。

项目成果

Inflammatory effects of highly pathogenic H5N1 influenza virus infection in the CNS of mice.

• DOI: 10.1523/jneurosci.5123-11.2012
• 发表时间: 2012-02-01
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Jang H;Boltz D;McClaren J;Pani AK;Smeyne M;Korff A;Webster R;Smeyne RJ
• 通讯作者: Smeyne RJ