Funded Studies
Objective/Rationale:
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. Recently, our lab has shown that exposure to the H5N1 influenza virus can induce a parkinsonian pathology. Here we will determine if the influenza virus responsible for the current pandemic (H1N1) can also induce these pathologies or if the induced parkinsonism is specific to individual viral strains.
Project Description:
This study will be done in mice. These animals will be infected with the most common form of H1N1 (strain A/H1N1/CA/04/2009) influenza virus via an intranasal route. We will then determine when and how H1N1 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 mice 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, HPLC, and immunological measurements using a microbead assay
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 previous studies with the H5N1 influenza virus, we know that certain strains of influenza can induce aspects of parkinsonism including cell loss, activation of the immune system within the nervous system and increases in the expression of alpha-synuclein. In this study we will learn if these induced pathologies are specific to H5N1 or if they are a general reaction to other influenza viruses, both those that are neurotropic and those that are not. We will also learn if immune activation of the brain, a common pathology seen in PD, can only be induced by a direct intra-CNS insult or if humoral cytokine expression can also induce the activation of the intrinsic CNS immune system.
Final Outcome
Previous studies have demonstrated that the H5N1 influenza virus can enter the nervous system and induce parkinsonism in pre-clinical and clinical models. Here, we examined if the H1N1 influenza virus, responsible for the pandemic influenza outbreak of 2009, was neurotrophic and could induce similar CNS pathologies. We determined that the H1N1-2009 virus did not enter the CNS, PNS or ENS, nor induce the loss of SNpc dopaminergic neurons. However, despite the lack of physical entry to the nervous system, the H1N1 virus induces an inflammatory response in the basal ganglia characterized by an increase in the number and size of microglia in the substantia nigra and an upregulation of genes in this pathway. The long-term effects of this inflammation still need to be determined.