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Journal of Virology, December 2003, p. 13203-13213, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.13203-13213.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Infection and Injury of Neurons by West Nile Encephalitis Virus

Bimmi Shrestha,1 David Gottlieb,2 and Michael S. Diamond1,3,4*

Departments of Medicine,1 Pathology and Immunology,3 Molecular Microbiology,4 Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri2

Received 27 June 2003/ Accepted 12 September 2003

West Nile virus (WNV) infects neurons and leads to encephalitis, paralysis, and death in humans, animals, and birds. We investigated the mechanism by which neuronal injury occurs after WNV infection. Neurons in the anterior horn of the spinal cords of paralyzed mice exhibited a high degree of WNV infection, leukocyte infiltration, and degeneration. Because it was difficult to distinguish whether neuronal injury was caused by viral infection or by the immune system response, a novel tissue culture model for WNV infection was established in neurons derived from embryonic stem (ES) cells. Undifferentiated ES cells were relatively resistant to WNV infection. After differentiation, ES cells expressed neural antigens, acquired a neuronal phenotype, and became permissive for WNV infection. Within 48 h of exposure to an exceedingly low multiplicity of infection (5 x 10-4), 50% of ES cell-derived neurons became infected, producing nearly 107 PFU of infectious virus per ml, and began to die by an apoptotic mechanism. The establishment of a tractable virus infection model in ES cell-derived neurons facilitates the study of the molecular basis of neurotropism and the mechanisms of viral and immune-mediated neuronal injury after infection by WNV or other neurotropic pathogens.

* Corresponding author. Mailing address: Departments of Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave., Box 8051, St. Louis, MO 63110. Phone: (314) 362-2842. Fax: (314) 362-9230. E-mail: diamond{at}borcim.wustl.edu.

Journal of Virology, December 2003, p. 13203-13213, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.13203-13213.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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