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West Nile virus—induced acute flaccid paralysis is prevented by monoclonal antibody treatment when administered after infection of spinal cord neurons

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Abstract

Acute flaccid polio-like paralysis occurs during natural West Nile virus (WNV) infection in a subset of cases in animals and humans. To evaluate the pathology and the possibility for therapeutic intervention, the authors developed a model of acute flaccid paralysis by injecting WNV directly into the sciatic nerve or spinal cord of hamsters. By directly injecting selected sites of the nervous system with WNV, the authors mapped the lesions responsible for hind limb paralysis to the lumbar spinal cord. Immunohistochemical analysis of spinal cord sections from paralyzed hamsters revealed that WNV-infected neurons localized primarily to the ventral motor horn of the gray matter, consistent with the polio-like clinical presentation. Neuronal apoptosis and diminished cell function were identified by TUNEL (terminal deoxynucleotidyl transferase—mediated BrdUTP nick end labeling) and choline acetyltransferase staining, respectively. Administration of hE16, a potently neutralizing humanized anti-WNV monoclonal antibody, 2 to 3 days after direct WNV infection of the spinal cord, significantly reduced paralysis and mortality. Additionally, a single injection of hE16 as late as 5 days after WNV inoculation of the sciatic nerve also prevented paralysis. Overall, these experiments establish that WNV-induced acute flaccid paralysis in hamsters is due to neuronal infection and injury in the lumbar spinal cord and that treatment with a therapeutic antibody prevents paralysis when administered after WNV infection of spinal cord neurons.

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Authors and Affiliations

  1. Institute for Antiviral Research, Animal, Dairy, and Veterinary Sciences Department, Utah State University, 4700 Old Main Hill, 84322-4700, Logan, UT, USA

    John D. Morrey, Venkatraman Siddharthan, Hong Wang, Jeffery O. Hall, Ramona T. Skirpstunas & Aaron L. Olsen

  2. MacroGenics, Inc., Rockville, Maryland, USA

    Jeffrey L. Nordstrom, Scott Koenig & Syd Johnson

  3. Departments of Molecular Microbiology, Medicine, and Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    Michael S. Diamond

Authors
  1. John D. Morrey
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  2. Venkatraman Siddharthan
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  3. Hong Wang
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  4. Jeffery O. Hall
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  5. Ramona T. Skirpstunas
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  6. Aaron L. Olsen
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  7. Jeffrey L. Nordstrom
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  8. Scott Koenig
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  9. Syd Johnson
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  10. Michael S. Diamond
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Corresponding author

Correspondence to John D. Morrey.

Additional information

Funding. NIH NO1-AI-15435 (J.D.M.) Virology Branch, NIAID, NIH; 1-U54 AI06357-01 Rocky Mountain Regional Centers of Excellence (J.D.M.); U01-AI061373 (M.S.D.), and NIAID, NIH, DPHS Contract No. HHSN266200600013C (MacroGenics).

Conflict of interest. V.S., A.L.O., H.W., J.O.H., R.T.S. do not have any conflict of interest. S.K., S.J., and J.L.N. are employees of MacroGenics Inc., and the company has rights to commercialize the monoclonal antibody described in this article. M.S.D. and J.D.M. have consulting agreements with MacroGenics Inc.

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Morrey, J.D., Siddharthan, V., Wang, H. et al. West Nile virus—induced acute flaccid paralysis is prevented by monoclonal antibody treatment when administered after infection of spinal cord neurons. Journal of NeuroVirology 14, 152–163 (2008). https://doi.org/10.1080/13550280801958930

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  • DOI: https://doi.org/10.1080/13550280801958930

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