Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion

Alvaro Arjona, Harald G. Foellmer, Terrence Town, Lin Leng, Courtney McDonald, Tian Wang, Susan J. Wong, Ruth R. Montgomery, Erol Fikrig, Richard Bucala

Research output: Contribution to journalArticle

112 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3059-3066
Number of pages8
JournalJournal of Clinical Investigation
Volume117
Issue number10
DOIs
StatePublished - Oct 1 2007

ASJC Scopus subject areas

  • Medicine(all)

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