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

J.Clin. Invest. 117:3059-3066 (2007).

Speaker: 黃偉誠                                   Time: 15:00 – 16:00, Nov. 28, 2007

Commentator: 葉才明 老師                        Place : Room 601

Abstract:

West Nile virus¹ (WNV) belongs to flaviviruses and causes severe fatal encephalitis in humans. Macrophage migration inhibitory factor (MIF)^2,3 identified nearly four decades ago is a constitutively expressed cytokine and mainly expressed by leukocytes. MIF promotes the pro-inflammatory functions of immune cells and is increased in several viral infections, yet the roles of MIF in infections are still unclear. In this study, the authors found that high levels of MIF were induced in the plasma and brains of WNV-infected patients. Similarly, in an established murine model, MIF was induced after WNV infection in the periphery and brains with the highest levels at days 2 and 6 post-infection, respectively. To determine the roles of MIF in WNV infection, they used the MIF inhibitor, MIF-neutralizing antibody, and Mif^-/- mice and found that, when MIF was reduced, the survival of WNV-infected mice was increased. However, the viral loads in the Mif^-/- mouse brains were reduced, but there were no marked differences in viral loads in the spleens after WNV infection compared to WT mice. Furthermore, they also found that the levels of inflammatory cytokines (such as IFN-α, TNF-α, and IL-6) were reduced in the brains but not in the spleens of Mif^-/- mice after infection, and the permeability of the blood-brain barrier was also decreased in infected Mif^-/- mice. Collectively, MIF promotes WNV neuroinvasion through modulating the permeability of blood-brain-barrier. In the future, MIF may serve as a therapeutic target of WNV encephalitis.

References:

1.         Davis, L.E., et al. West Nile virus neuroinvasive disease. Annals of neurology 60, 286-300 (2006).

2.         Calandra, T., Bernhagen, J., Mitchell, R.A. & Bucala, R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. The Journal of experimental medicine 179, 1895-1902 (1994).

3.         Calandra, T. & Roger, T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nature reviews 3, 791-800 (2003).