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.
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.