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Journal of Virology, October 2007, p. 10933-10949, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.02422-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

West Nile Virus-Induced Neuroinflammation: Glial Infection and Capsid Protein-Mediated Neurovirulence{triangledown}

Guido van Marle,1 Joseph Antony,2 Heather Ostermann,3 Christopher Dunham,2 Tracey Hunt,4 William Halliday,5 Ferdinand Maingat,7 Matt D. Urbanowski,4 Tom Hobman,4 James Peeling,3 and Christopher Power1,2,6,7*

Departments of Microbiology and Infectious Diseases,1 Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada,2 Departments of Pharmacology and Therapeutics and Radiology, University of Manitoba, Winnipeg, Manitoba, Canada,3 Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada,5 Departments of Cell Biology,4 Medical Microbiology and Immunology,6 Medicine, University of Alberta, Edmonton, Alberta, Canada7

Received 3 November 2006/ Accepted 3 July 2007

West Nile virus (WNV) infection causes neurological disease at all levels of the neural axis, accompanied by neuroinflammation and neuronal loss, although the underlying mechanisms remain uncertain. Given the substantial activation of neuroinflammatory pathways observed in WNV infection, we hypothesized that WNV-mediated neuroinflammation and cell death occurred through WNV infection of both glia and neurons, which was driven in part by WNV capsid protein expression. Analysis of autopsied neural tissues from humans with WNV encephalomyelitis (WNVE) revealed WNV infection of both neurons and glia. Upregulation of proinflammatory genes, CXCL10, interleukin-1ß, and indolamine-2',3'-deoxygenase with concurrent suppression of the protective astrocyte-specific endoplasmic reticulum stress sensor gene, OASIS (for old astrocyte specifically induced substance), was evident in WNVE patients compared to non-WNVE controls. These findings were supported by increased ex vivo expression of these proinflammatory genes in glia infected by WNV-NY99. WNV infection caused endoplasmic reticulum stress gene induction and apoptosis in neurons but did not affect glial viability. WNV-infected astrocytic cells secreted cytotoxic factors, which caused neuronal apoptosis. The expression of the WNV-NY99 capsid protein in neurons and glia by a Sindbis virus-derived vector (SINrep5-WNVc) caused neuronal death and the release of neurotoxic factors by infected astrocytes, coupled with proinflammatory gene induction and suppression of OASIS. Striatal implantation of SINrep5-WNVC induced neuroinflammation in rats, together with the induction of CXCL10 and diminished OASIS expression, compared to controls. Moreover, magnetic resonance neuroimaging showed edema and tissue injury in the vicinity of the SINrep5-WNVc implantation site compared to controls, which was complemented by neurobehavioral abnormalities in the SINrep5-WNVc-implanted animals. These studies underscore the important interactions between the WNV capsid protein and neuroinflammation in the pathogenesis of WNV-induced neurological disorders.

* Corresponding author. Mailing address: Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Phone: (780) 407-1938. Fax: (780) 407-1984. E-mail: chris.power{at}ualberta.ca

{triangledown} Published ahead of print on 1 August 2007.

Journal of Virology, October 2007, p. 10933-10949, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.02422-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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