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）：帕金森病的病因是多方面的，从确定的基因突变到严格的环境原因。帕金森氏病也可能发生在接触病毒后，包括流感病毒。大多数人类流感感染会导致上呼吸道感染，但偶尔会影响大脑。在这个时候，有相当大的威胁，一个世界性的流行病从H5 N1株流感病毒，所谓的“禽流感”。此前，由H1N1流感病毒引起的1918年流感大流行影响了世界25-30%的人口，造成4000多万人死亡。在幸存的人群中，大流行与昏睡性脑炎（Von Economo病）的爆发有关，随后是脑后帕金森病的高峰。我们的初步结果表明，H5 N1病毒是嗜神经的，可以感染各种中枢神经系统和PNS地区。然而，目前尚不清楚H5 N1病毒是否会引起特定的神经损伤。由于H5 N1病毒有可能发生突变并开始人传人（可能导致全球流感大流行），因此在哺乳动物物种中检查这种病毒是否有能力导致脑后神经退行性疾病，特别是诱导帕金森症，这是至关重要的。在本申请中，我们提出了三个具体目标。具体目标1将确定鼻内接种后小鼠中枢、外周和肠神经系统中H5 N1流感病毒感染的时间进程。在此，我们将使用H5 N1病毒的免疫组织化学检测来绘制H5 N1鼻内给药后1、3、7、10、21、28、60和90天H5 N1的存在。我们还将检查H5 N1感染的细胞（神经元，星形胶质细胞，小胶质细胞，上皮细胞）以及确定病毒如何进入神经系统。具体目标2将凭经验确定H5 N1流感病毒感染是否导致其靶纹状体中SNpc神经元的损失或多巴胺的消耗，以及H5 N1的存在是否诱导免疫反应，具体目标3将确定H5 N1流感病毒的先前CNS感染是否增加对帕金森毒素MPTP的敏感性。公共卫生相关性：未来人类流感大流行的时间、毒力和总体范围存在很大的不确定性。然而，H5 N1最近表现出相当大的流行潜力。大流行性流感病毒株必须具备3个特征：1）它必须是一种以前从未在人类中见过的新流感病毒株; 2）它必须能够在人类中复制并引起疾病; 3）它必须在人与人之间有效传播。H5 N1已经符合前两个特征。此外，它现在正通过鸟类种群在世界范围内传播，可能在许多地区成为地方病，从而增加了人类接触的风险。如果发生H5 N1人类大流行，对人口的影响将是巨大的。对预计伤亡人数的估计差异很大，全世界从200万到3.6亿不等，这取决于对病毒致命性的假设，随着病毒适应人类，这种假设可能会有很大差异（世卫组织网站）。然而，显而易见的是，世界人口的很大一部分将受到感染。根据H5 N1嗜神经性的报告，包括我们的初步研究（见下文），奥利弗萨克斯在纽约时报上发表的一篇专栏文章特别具有预言性。在这里，他写道“...我们最好重新认识到，这种疾病不仅对人类生命，而且对那些感染H5 N1流感后仍能存活的人的大脑构成巨大威胁”。

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