Objective/Rationale:
There is a significant literature (mostly based on cases from the Spanish Influenza outbreak of 1918) that has documented Parkinson’s disease occurring, following exposure to influenza. Viruses (including influenza) have also been proposed to be an etiological agent for PD based on the appearance of otherwise non-explained clusters of parkinsonism. Here we will test the hypothesis that highly pathogenic H5N1 ("bird-flu") influenza virus, which poses the greatest pandemic flu risk today, is an etiological agent for induction of parkinsonism.
Project Description:
This study will be done in laboratory models. These models will be infected with the most common form of H5N1 influenza virus via an intranasal route. We will then determine when and how H5N1 infects the nervous system. Specifically, we want to determine both the progression of the infection and its sequalae in the nervous system. We will examine models both early in the infectious stage (days 0-21) as well as long after the infection subsides (days 30-120) to see both the acute and chronic effects of influenza infection including effects on substantia nigra cell number, effects on dopamine levels thoughout the brain, as well as induction and aggregation of alpha-synuclein . We will use a number of techniques to examine these parameters including immunohistochemistry, electron microscopy, HPLC and ELISA.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Although this work will not directly impact the way Parkinson’s disease is treated, the experiments in this proposal will directly test the hypothesis that viruses, specifically influenza viruses, can directly or secondarily influence the onset and/or progression of Parkinson’s disease.
Anticipated Outcome:
Based on our preliminary experiments, we expect to show that influenza virus can induce aspects of parkinsonism including cell loss and activation of the immune system within the nervous system. We also expect to be able to show how viruses access the nervous system, which have been hypothesized to be via the vagus and olfactory bulb. If these prove to be the route of entry, they may support the hypothesis by Braak that Parkinson’s disease is disorder that affects both the peripheral and central nervous systems in a highly stereotypical progression.
Final Outcome
Both humans and animals infected by H5N1 virus demonstrate acute neurological signs and motor symptoms that resemble those seen in parkinsonian patients. To test if H5N1 viral infection is a proximate cause of parkinsonism, we intranasally inoculated laboratory models with H5N1 influenza virus and analyzed the pathological outcomes.
About 50 percent of the infected models became ataxic, bradykinetic and had postural abnormalities. We also found that the H5N1 virus could directly infect the brain, most likely traveling from the enteric and peripheral nervous systems into the CNS. Once in the CNS, the pattern of infection progressed from brainstem to cortex.
Examination of the basal ganglia showed a transient but significant loss of dopaminergic neurons in the substantia nigra pars compacta and loss of striatal dopamine that persisted through day 90 post infection. In regions of the brain infected by H5N1, we also observed alpha-synuclein aggregation. Our results suggest that a pandemic H5N1 pathogen, or other neurotropic influenza virus, could initiate CNS disorders of protein aggregation including Parkinson’s disease.