Abstract
The molecular basis for the increased resistance of astrocytes to a non-neuropathogenic strain of West Nile virus (WNV), WNV-MAD78, compared with the neuropathogenic strain WNV-NY remains unclear. Here, we demonstrated that the reduced susceptibility of astrocytes to WNV-MAD78 is due to a combination of both cellular activities as well as viral determinants. Analyses of the viral particle indicated that astrocyte-derived WNV-MAD78 particles were less infectious than those of WNV-NY. Additionally, inhibition of cellular furin-like proteases increased WNV-MAD78 infectious particle production in astrocytes, suggesting that high levels of furin-like protease activity within these cells acted in a cell- and strain-specific manner to inhibit WNV-MAD78 replication. Moreover, analysis of recombinant viruses indicated that the structural proteins of WNV-MAD78 were responsible for decreased particle infectivity and the corresponding reduction in infectious particle production compared with WNV-NY. Thus, the composition of the WNV virion was also a major determinant for viral fitness within astrocytes and may contribute to WNV propagation within the central nervous system. Whether the WNV-MAD78 structural genes reduce virus replication and particle infectivity through the same mechanism as the cellular furin-like protease activity or whether these two determinants function through distinct pathways remains to be determined.
Highlights
West Nile virus (WNV) is a neurotropic member of the genus Flavivirus that has emerged recently as a significant threat to human health
To determine if another secreted factor contributes to the reduction in WNV-MAD78 replication, we assessed the inhibitory potential of supernatant collected from WNVinfected astrocytes
Human brain cortical astrocytes (HBCAs) were treated with UV-inactivated supernatants recovered from mock, WNV-NY- or WNV-MAD78infected HBCAs
Summary
West Nile virus (WNV) is a neurotropic member of the genus Flavivirus that has emerged recently as a significant threat to human health. Recent outbreaks in the Western hemisphere have been characterized by a marked increase in the percentage of neurological infections. The viral factors responsible for the increased incidence of neurological disease associated with these recent outbreaks remain poorly understood. Once sufficient levels of viral proteins and nascent RNA genomes accumulate, immature particles, which consist of the viral genome surrounded by the capsid (C), precursor membrane (prM) and E proteins, assemble at the endoplasmic reticulum membrane. During egress through the secretory pathway, cleavage of prM by furin-like proteases promotes conformational changes to the global structure of the virion, which leads to the formation of the mature virus particle. As the virion is released into the extracellular milieu, the cleaved precursor portion dissociates, completing the maturation process
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