Date of Award

5-2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Neuroscience

Research Advisor

Richard J. Smeyne, Ph.D.

Committee

Kristin M. Hamre, Ph.D. Michael C. Levin, Ph.D. James I. Morgan, Ph.D. Richard J. Webby, Ph.D

Keywords

alpha-synuclein, encephalitis, influenza, neurodegeneration, neuroinflammation, Parkinson's disease

Abstract

The greatest threat for an influenza pandemic at this time is posed by the highly pathogenic H5N1 avian influenza virus. To date, 63% of the 436 known human cases of H5N1 infection have proven fatal. Animals infected by H5N1 viruses have demonstrated acute neurological signs ranging from mild encephalitis to motor disturbances and coma. However, no studies have examined the longer-term neurologic consequences of H5N1 infection. We show that this virus travels from the peripheral nervous system into the central nervous system (CNS) to higher levels of the neuroaxis, using C57BL/6J mice that are infected by the A/VN/1203/04 H5N1 virus (without adaptation). In regions infected by H5N1 virus, we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection.

To determine if the pathology worsened with age, we examined: 1) substantia nigra pars compacta (SNpc) tyrosine hydroxylase positive dopaminergic neuron number and striatal dopamine and its metabolites contents through 90 days post infection (dpi), 2) examined the inflammatory effect of infection by quantitatively measuring the total number of resting and activated microglia in the SNpc and then examined the production of cytokines in regions of the brain infected by H5N1. We found that infection with H5N1 induces a reversible reduction of both the number of dopaminergic neurons in the SNpc and the amount of dopamine and its metabolites in the striatum. Examination of other indolamines demonstrated a significant and sustained reductionof serotonin in regions of the brain infected with H5N1. We also observed that areas of the brain infected with H5N1 expressed altered levels of pro-inflammatory cytokines, chemokines and growth factors.

We examined if H5N1 priming potentiates paraquat (PQ) induced neurotoxicity in the basal ganglia. We found that H5N1 priming did not increase the sensitivity of C57BL/6J mice to intraperitoneal (ip) administration of paraquat. Rather, H5N1 priming protects the dopaminergic neurons from PQ-induced neurodegeneration and diminishes immune response produced by PQ in the CNS.

DOI

10.21007/etd.cghs.2010.0151

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