Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion
Alvaro Arjona, … , Erol Fikrig, Richard Bucala
Alvaro Arjona, … , Erol Fikrig, Richard Bucala
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):3059-3066. https://doi.org/10.1172/JCI32218.
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Research Article Infectious disease

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

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

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Figure 1

WNV infection induces MIF expression.

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WNV infection induces MIF expression. (A) MIF plasma levels of patients ...
(A) MIF plasma levels of patients suffering from acute WNV infection (n = 27) and control donors (n = 31). The distribution of data points in each group is represented by box-and-whisker plots, where horizontal lines mark (from the bottom up) the 25th, 50th (median), and 75th percentiles. The central vertical line in each box represents the range of values (5th–95th percentiles). (B) MIF levels in the CSF of WNV-infected patients (n = 7) and controls (n = 5). MIF mRNA levels were determined by Q-PCR in the brain (C) and spleen (D) of WT BALB/c mice at days 0, 2, 4, 6, and 8 after i.p. inoculation of WNV. Data are mean ± SEM of 3–6 mice per time point. (E) MIF serum levels determined by ELISA in WT BALB/c mice at days 0, 2, 4, 6, and 8 after i.p. inoculation of WNV. Data are mean ± SEM of 3–6 mice per time point. *P < 0.05, per Student’s t test. Data from mice were pooled from 2 independent experiments (3 mice per time point and experiment).