title: Does astroglial protein S100B contribute to West Nile neuro-invasive syndrome?
abstract: The clinical spectrum of West Nile Virus (WNV) infection ranges from a flu-like febrile condition to a more severe neuro-invasive disease that can cause death. The exact mechanism of neurodegeneration in neuro-invasive form of WNV infection has not been elucidated; however, a destructive role played by glial cells in promoting WNV mediated neurotoxicity has widely been speculated. The clinical studies revealed that the astroglial protein S100B is significantly elevated in the blood and CSF of patients with WNV infection, even in the absence of neuro-invasive disease. Therefore, the present study was designed to explore the potential role of S100B in the pathophysiology of WNV infection. The overarching hypothesis was that WNV primes astroglia to release S100B protein, which leads to a cascade of events that may have deleterious effects in both acute and chronic stages of WNV disease. To justify our hypothesis, we first ascertained increased levels of S100B in post-mortem tissue samples from WNV patients. Next, we looked at the effects of UV-inactivated WNV particles on astroglia using astroglial cell lines or primary cultures. Astroglial activation was measured as an increase in the expression of S100B and was analyzed by immunofluorescence and real-time PCR. Further, the in vitro effects of purified S100B protein on neutrophil migration and glutamate uptake were also determined in astroglial cell lines or primary cultures. We found that incubation of cultured astroglial cells with UV-inactivated WNV particles caused induction of S100B both at the mRNA and protein levels. Varying concentrations of S100B stimulated neutrophil migration in vitro. In addition, varying amounts of S100B caused inhibition of glutamate uptake in astroglia in a dose-dependent manner. Our data suggest that inactivated WNV particles are capable of inducing S100B synthesis in astroglia in vitro. We speculate that S100B release by activated astroglia may have multiple roles in the pathophysiology of WNV neuro-invasive disease, including induction of neutrophil migration to the sites where blood brain barrier is disrupted as well as glutamate neurotoxicity. To further elucidate the WNV-S100B neurotoxic pathway, in vivo studies using mouse models are warranted.
authors.affiliation: Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, USA; Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Kuwar
authors.affiliation: Methodist Rehabilitation Center, Jackson, Mississippi, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Stokic
authors.affiliation: Methodist Rehabilitation Center, Jackson, Mississippi, USA; Department of Neurology, Mayo Clinic, Arizona, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Leis
authors.affiliation: Department of Biological Sciences, University of Southern Mississippi, Hattiesburg, Mississippi, USA.
authors.forename: F
authors.initials: F
authors.lastname: Bai
authors.affiliation: Department of Biological Sciences, University of Southern Mississippi, Hattiesburg, Mississippi, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Paul
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Fratkin
authors.affiliation: Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, USA; Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, Mississippi, USA; Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi, USA. Electronic address: pvig@umc.edu.
authors.forename: P J S
authors.initials: PJ
authors.lastname: Vig
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism*; D014901:West Nile Fever / Q000378:metabolism* / Q000473:pathology; D014902:West Nile virus
chemical_list: D064568:S100 Calcium Binding Protein beta Subunit; D018698:Glutamic Acid
keywords: Astrocytes; Glutamate; Neurodegeneration; Neutrophils; S100B; West Nile