Immune Responses to West Nile Virus Infection in the Central Nervous System

Departments of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. .
Viruses (Impact Factor: 3.35). 12/2012; 4(12):3812-30. DOI: 10.3390/v4123812
Source: PubMed


West Nile virus (WNV) continues to cause outbreaks of severe neuroinvasive disease in humans and other vertebrate animals in the United States, Europe, and other regions of the world. This review discusses our understanding of the interactions between virus and host that occur in the central nervous system (CNS), the outcome of which can be protection, viral pathogenesis, or immunopathogenesis. We will focus on defining the current state of knowledge of WNV entry, tropism, and host immune response in the CNS, all of which affect the balance between injury and successful clearance.

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    • "WNV primarily enters the central nervous system (CNS) by crossing the blood–brain barrier (BBB) (Cho & Diamond, 2012; Hussmann et al., 2013; Roe et al., 2012; Verma et al., 2009). The BBB is a highly restrictive barrier that protects the CNS from aberrant immune responses and pathogens in the periphery (Abbott, 2002). "
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    ABSTRACT: The molecular basis for the increased resistance of astrocytes to a nonneuropathogenic strain of WNV, WNV-MAD78, compared to the neuropathogenic strain WNV-NY remains unclear. In this report, we demonstrate 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 are 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 acts 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 to WNV-NY. Thus, the composition of the WNV virion is also a major determinant for viral fitness within astrocytes and may contribute to WNV propagation within the CNS. 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.
    Full-text · Article · Jun 2014 · Journal of General Virology
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    • "The West Nile virus (WNV) is an epidemic neurotropic virus estimated to be responsible of about 36,000 cases and 1,500 deaths registered in the United States between 1992 and 2012 [86]. WNV antigenicity allows its classification into the Japanese encephalitis virus (JEV) serocomplex. "
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    ABSTRACT: More than 150 arboviruses belonging to different families are known to infect humans, causing endemic infections as well as epidemic outbreaks. Effective vaccines to limit the occurrence of some of these infections have been licensed, while for the others several new immunogens are under development mostly for their improvements concerning safety and effectiveness profiles. On the other hand, specific and effective antiviral drugs are not yet available, posing an urgent medical need in particular for emergency cases. Neutralizing monoclonal antibodies (mAbs) have been demonstrated to be effective in the treatment of several infectious diseases as well as in preliminary in vitro and in vivo models of arbovirus-related infections. Given their specific antiviral activity as well-tolerated molecules with limited side effects, mAbs could represent a new therapeutic approach for the development of an effective treatment, as well as useful tools in the study of the host-virus interplay and in the development of more effective immunogens. However, before their use as candidate therapeutics, possible hurdles (e.g., Ab-dependent enhancement of infection, occurrence of viral escape variants) must be carefully evaluated. In this review are described the main arboviruses infecting humans and candidate mAbs to be possibly used in a future passive immunotherapy.
    Full-text · Article · Aug 2013
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    • "WNV, an arthropod-borne flavivirus, causes encephalitis and meningitis in a small percentage of infected humans after the initial replication in keratinocytes and Langerhans cells in the skin (Lim et al., 2011). CNS infections often are associated with inefficient immune clearance of infection in the peripheral tissues and the resulting robust virus replication and subsequent viremia (Cho and Diamond, 2012). WNV can access the CNS either by infecting sensory nerve endings or olfactory neurons or through blood circulation, but not via NMJs (Lim et al., 2011). "
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    ABSTRACT: Virus infections usually begin in peripheral tissues and can invade the mammalian nervous system (NS), spreading into the peripheral (PNS) and more rarely the central (CNS) nervous systems. The CNS is protected from most virus infections by effective immune responses and multilayer barriers. However, some viruses enter the NS with high efficiency via the bloodstream or by directly infecting nerves that innervate peripheral tissues, resulting in debilitating direct and immune-mediated pathology. Most viruses in the NS are opportunistic or accidental pathogens, but a few, most notably the alpha herpesviruses and rabies virus, have evolved to enter the NS efficiently and exploit neuronal cell biology. Remarkably, the alpha herpesviruses can establish quiescent infections in the PNS, with rare but often fatal CNS pathology. Here we review how viruses gain access to and spread in the well-protected CNS, with particular emphasis on alpha herpesviruses, which establish and maintain persistent NS infections.
    Full-text · Article · Apr 2013 · Cell host & microbe
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