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"""""""".

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Sieber, Beth-Anne
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St. Jude Children's Research Hospital
United States
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Jang, Haeman; Boltz, David; McClaren, Jennifer et al. (2012) Inflammatory effects of highly pathogenic H5N1 influenza virus infection in the CNS of mice. J Neurosci 32:1545-59
Henry, Julia; Smeyne, Richard J; Jang, Haeman et al. (2010) Parkinsonism and neurological manifestations of influenza throughout the 20th and 21st centuries. Parkinsonism Relat Disord 16:566-71
Jang, Haeman; Boltz, David; Sturm-Ramirez, Katharine et al. (2009) Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci U S A 106:14063-8