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

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.

Persistent West Nile Virus Associated with a Neurological Sequela in Hamsters Identified by Motor Unit Number Estimation

“…10A). TUNEL staining was apparent in the nuclei of some, but not all neurons; however, the TUNEL staining did not subjectively appear to be as intense as in the acute infection (24,33) (Fig. 10C).…”

“…The utility of MUNE elucidated mechanisms of pathogenesis in this neurological sequela, namely, that WNV antigen or virus can persist in neurons to cause dysfunction, that WNV is associated with chronic neuropathological lesions, and that this neurological sequela is nearly a universal event in WNVinfected hamsters under the conditions investigated. ␣-Motor neurons, large motor neurons in the anterior horn of the spinal cord (ventral horn in horizontal animals), are one of the primary targets in ALS (5), poliovirus (21), and for WNV (24). More specifically, WNV has been described as causing poliomyelitis-like disease, since it infects motor neurons in the anterior horn of the spinal cord (10,24).…”

“…10) and H&E staining (see Fig. 5 and 7), cardiac perfusion with phosphate-buffered saline followed by 200 ml of freshly prepared 4% paraformaldehyde was performed (24). Paraffinized sections were processed using primary monoclonal antibody 7H2 against WNV (BioReliance, Invitrogen Bioservices, Rockville, MD) and Alexa Fluor 568 goat anti-mouse immunoglobulin G (IgG) antibody for WNV detection.…”

Activation of Innate Immune Responses in the Central Nervous System during Reovirus Myelitis

“…The progression of paralysis coincides with the spread of viral antigen to the contralateral side of the spinal cord and associated motor neuron death. Reovirus myelitis, like reovirus encephalitis, is associated with the apoptotic death of infected neurons, an association that is also seen in models of poliovirus and West Nile virus myelitis (26,30,53,63).…”

Infección por virus del Zika en el embarazo, impacto fetal y neonatal

“…Una de las rutas, es la disrupción de las uniones intercelulares herméticas (UIH), a través de la alteración de la claudina 26,27 , un componente esencial de estas UIH, promoviendo el transporte de los FV que se encuentran libres o dentro de los linfocitos o neutrófilos (fenómeno conocido como caballo de Troya) a través de la barrera hemato-encefálica (BHE), los plexos coroides y la glía (astrocitos y microglia) 28,29 . La otra ruta de neuroinvasión de los FV es el resultado del transporte axonal neuronal en dirección antero y retrógrada desde la periferia (durante la viremia) a través de la médula espinal o el bulbo olfatorio, dando lugar a la apoptosis de la neurona anterior del cuerno espinal, siendo compatible con los datos de parálisis flácida aguda 30,31 . Se han considerado como potenciales receptores para la entrada de los FV al SNC, los receptores transmembrana, tipo RMM (receptor de membrana de manosa) en los astrocitos y microglía 32 y el DC-SIGN o CD209 (Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) en las células dendríticas, células perivasculares del SNC y de los vasos cerebrales 32 ; sin embargo, estos receptores son improbables candidatos, debido, a que ellos no son expresados por las neuronas ni por los axones de los nervios periféricos 33,34 .…”