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

Abstract

To investigate the hypothesis that neurological sequelae are associated with persistent West Nile virus (WNV) and neuropathology, we developed an electrophysiological motor unit number estimation (MUNE) assay to measure the health of motor neurons temporally in hamsters. The MUNE assay was successful in identifying chronic neuropathology in the spinal cords of infected hamsters. MUNE was suppressed at days 9 to 92 in hamsters injected subcutaneously with WNV, thereby establishing that a long-term neurological sequela does occur in the hamster model. MUNE suppression at day 10 correlated with the loss of neuronal function as indicated by reduced choline acetyltransferase staining (R 2 ‫؍‬ 0.91). Between days 10 and 26, some ␣-motor neurons had died, but further neuronal death was not detected beyond day 26. MUNE correlated with disease phenotype, because the lowest MUNE values were detected in paralyzed limbs. Persistent WNV RNA and foci of WNV envelope-positive cells were identified in the central nervous systems of all hamsters tested from 28 to 86 days. WNV-positive staining colocalized with the neuropathology, which suggested that persistent WNV or its products contributed to neuropathogenesis. These results established that persistent WNV product or its proteins cause dysfunction, that WNV is associated with chronic neuropathological lesions, and that this neurological sequela is effectively detected by MUNE. Inasmuch as WNV-infected humans can also experience a poliomyelitis-like disease where motor neurons are damaged, MUNE may also be a sensitive clinical or therapeutic marker for those patients.

Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model

“…Hyperactivity is also observed during infection with borna disease virus, a neurotropic non-cytolytic RNA virus (Hornig et al, 1999). The infection pattern of ZIKV in the central nervous system was similar to that of the related flavivirus WNV that also infects motor neurons in the ventral horn of spinal cord (Siddharthan et al, 2009) and the brain stem (Morrey et al, 2010), although ZIKV infected cells generally co-localized with astroglial cells while WNV is more neuron-specific. We have also observed a similar infection of astroglial cells after Venezulan equine encephalitis virus infection in a C3H/HeN mouse model (Julander et al, 2008).…”

Evaluation of Prolonged Fatigue Post–West Nile Virus Infection and Association of Fatigue with Elevated Antiviral and Proinflammatory Cytokines

“…WNV causes a neuroinvasive disease in a small percentage of those infected (17) and can result in long-term mental and physical impairments (2,14,21). Extended IgM antibody titers have been documented several years postinfection in humans (22,26,28), and persistent neurologic and renal infection has been documented in animal models (25,30,31). Previous findings in this cohort have found persistence of IgM antibodies in 42%, 34%, and 23% of WNV-positive study participants approximately 1, 6, and 8 years postinfection, respectively (19).…”

Persistence of Detectable Immunoglobulin M Antibodies Up to 8 Years After Infection with West Nile Virus

“…Persistent infection with WNV has been well-documented in multiple species, including humans. [17][18][19][20][21][22] Hepatitis C virus (HCV) is also a member of the Flaviviridae family, and presence of IgM anti-HCV antibodies serves as a marker of active viral replication and associated liver disease during the chronic stage of infection. 23 Biologically, this association is understandable, and our finding of persistent IgM in WNV-infected patients leads to an urgent need to further document and understand the pathology of persistent WNV infection in humans.…”