The Neuroinvasion and Neuropathology of West Nile virus

Rebecca Biron (2009). The Neuroinvasion and Neuropathology of West Nile virus PhD Thesis, School of Chemistry & Molecular Bioscience, The University of Queensland.

       
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Author Rebecca Biron
Thesis Title The Neuroinvasion and Neuropathology of West Nile virus
School, Centre or Institute School of Chemistry & Molecular Bioscience
Institution The University of Queensland
Publication date 2009-09
Thesis type PhD Thesis
Supervisor Associate Professor Roy hall
Dr Matt Sweet
Total pages 216
Total colour pages 8
Total black and white pages 208
Subjects 06 Biological Sciences
Abstract/Summary West Nile Virus (WNV) has emerged as a major cause of viral encephalitis. Since its outbreak in the United States 27,000 people have presented with clinical WNV disease resulting in 1074 fatalities. WNV causes a range of disease from mild febrile illnesses to severe and fatal encephalitis. To date, there are currently no therapeutic agents or vaccines available to treat WNV infection in humans. In order to address this, a better understanding of the mechanisms responsible for viral neuroinvasion and neuropathology are required. Using a range of in vitro and in vivo studies, we have investigated the routes by which WNV enters the CNS. Virus replication was observed in the brain microvascular endothelial cells in mice that succumbed to WNV encephalitis. Moreover, we demonstrated that infection of a polarized HBMEC with WNV induced apoptosis. Microarray analysis of WNV-infected HBMEC’s revealed that WNV elicited the expression of cytokines that have been shown to contribute to permeablization of the BBB. These findings suggest that WNV can enter the CNS through the BBB via multiple mechanisms. Real-time RT-PCR performed on WNVinfected HBMECs identified two host genes involved in the host cellular anti-oxidant response that were differentially regulated during viral infection. Furthermore, the addition of the antioxidant, N-acetylcysteine, restored cell viability and decreased viral replication, indicating that oxidative stress contributes to WNV-induced pathogenesis. The current state of knowledge regarding the pathogenesis of WNV encephalitis is based on studies that have defined the role of systemic immune responses to WNV. Limited investigations have been undertaken to determine the contribution of brain cells in the defence, or damage to the brain once WNV has gained access to the CNS. Real-time RT-PCR results in conjunction with in vivo CBA assay data, suggested several candidate host genes that could contribute to the pathogenesis of WNV. Thus, it is necessary to further define the mechanisms of WNV induced pathogenesis as this will aid in the development of targeted strategies to prevent neurological infection and mitigate neurological diseases in affected individuals.
Keyword West Nile virus
neuroinvasion
neuropathology
blood-brain-barrier
Additional Notes pages 73-78 landscape pages 24, 26, 28, 29, 63, 66, 158, 162 printed in colour

 
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