title: Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion.
abstract: The flavivirus West Nile virus (WNV) is an emerging pathogen that causes life-threatening encephalitis in susceptible individuals. We investigated the role of the proinflammatory cytokine macrophage migration inhibitory factor (MIF), which is an upstream mediator of innate immunity, in WNV immunopathogenesis. We found that patients suffering from acute WNV infection presented with increased MIF levels in plasma and in cerebrospinal fluid. MIF expression also was induced in WNV-infected mice. Remarkably, abrogation of MIF action by 3 distinct approaches (antibody blockade, small molecule pharmacologic inhibition, and genetic deletion) rendered mice more resistant to WNV lethality. Mif(-/-) mice showed a reduced viral load and inflammatory response in the brain when compared with wild-type mice. Our results also indicate that MIF favors viral neuroinvasion by compromising the integrity of the blood-brain barrier. In conclusion, the data obtained from this study provide direct evidence for the involvement of MIF in viral pathogenesis and suggest that pharmacotherapeutic approaches targeting MIF may hold promise for the treatment of WNV encephalitis.
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Arjona
authors.forename: Harald G
authors.initials: HG
authors.lastname: Foellmer
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Courtney
authors.initials: C
authors.lastname: McDonald
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Wong
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Montgomery
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D019562:Viral Load; D053586:Virus Internalization; D014901:West Nile Fever / Q000235:genetics / Q000821:virology*; D014902:West Nile virus / Q000502:physiology*
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse