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，从已确定的基因突变到严格的环境原因。帕金森氏症也可能发生在接触了包括流感病毒在内的病毒之后。大多数人类感染流感会导致上呼吸道感染，但偶尔会影响大脑。目前，H5N1流感病毒株，即所谓的“禽流感”，有相当大的可能在全球范围内大流行。此前，1918年由H1N1流感病毒引发的大流感大流行影响了全球25%-30%的人口，导致4000多万人死亡。在幸存的人群中，大流行与昏睡性脑炎(冯·伊科诺莫病)的爆发有关，随后是脑后型帕金森病的激增。我们的初步结果表明，H5N1病毒是嗜神经性的，可以感染中枢神经系统和三叉神经节的各种区域。然而，目前尚不清楚H5N1病毒是否会导致特定的神经损伤。由于H5N1病毒有可能发生变异并开始人与人之间的传播(可能导致全球大流行流感)，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，特别是重点是诱发帕金森症，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将确定经鼻接种后H5N1流感病毒在小鼠中枢、外周和肠道神经系统感染的时间进程。在这里，我们将使用H5N1病毒的免疫组织化学检测来绘制H5N1鼻腔注射后1、3、7、10、21、28、60和90天的H5N1病毒存在图。我们还将检查哪些细胞会感染H5N1病毒(神经元、星形胶质细胞、小胶质细胞、上皮细胞)，并确定病毒如何进入神经系统。特定目标2将经验性地确定H5N1流感病毒感染是否会导致其目标纹状体SNPC神经元的丧失或多巴胺的耗竭，以及H5N1病毒的存在是否会诱导免疫反应，而特定目标3将确定先前感染H5N1流感病毒是否会增加对帕金森毒素MPTP的敏感性。与公共卫生相关：关于未来人类流感大流行的时间、毒性和总体范围存在很大的不确定性。然而，H5N1最近显示出相当大的大流行潜力。一个大流行性流感病毒株必须具备三个特征：1)它必须是一种在人类之前从未见过的新的流感病毒株；2)它必须能够复制并在人类身上引起疾病；3)它必须在人与人之间有效地传播。H5N1已经满足了前两个特征。此外，它现在正通过禽类种群在世界范围内传播，可能成为许多地区的地方性流行病，从而增加了人类接触的风险。如果发生H5N1人类大流行，对人类人口的影响将是巨大的。预计的伤亡人数差异很大，全世界从200万人到3.6亿人不等，这取决于对病毒致命性的假设，随着病毒适应人类的情况，这种假设可能会有很大差异(世卫组织网站)。然而，有一点是明确的，那就是世界上相当大比例的人口将被感染。根据关于H5N1嗜神经症的报道，包括我们的初步研究(见下文)，奥利弗·萨克斯在《纽约时报》上发表的一篇评论文章变得特别具有预见性38。在这里，他写道：“……我们最好重新认识到，这不仅是对人类生命的巨大威胁，而且对那些在H5N1流感感染中幸存下来的人的大脑也是如此。”

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