Pathogenic roles of macrophage migration inhibitory factor during dengue virus infection

Abstract

Dengue virus (DENV) infection is the most common cause of viral hemorrhagic fever, which can lead to life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Hemorrhage and plasma leakage are two major hallmarks of DHF/DSS. Because the mechanisms causing these pathogenic changes are unclear, there is no effective therapy against DHF/DSS. In this review, we focus on the possible pathogenic effects of a pleiotropic cytokine, macrophage migration inhibitory factor (MIF), on the pathogenesis of DENV infection. MIF is a critical mediator of the host immune response and inflammation, and there is a correlation between the serum levels of MIF and disease severity in dengue patients. Furthermore, MIF knock-out mice exhibit less severe clinical disease and lethality. However, the role of MIF in the pathogenesis of DHF/DSS is not limited to immune cell recruitment. Recent evidence indicates that DENV infection induced MIF production and may contribute to vascular hyperpermeability and viral replication during DENV infection. The expression of both adhesion and coagulation molecules on MIF-stimulated monocytes and endothelial cells is also increased, which may contribute to inflammatory and anticoagulatory states during DHF/DSS. Therefore, blocking MIF production or its function may provide a solution for the treatment and prevention of DHF/DSS.

Figure 1

Schematic diagram of the pathogenic roles of MIF and possible strategies to block its effects during DENV infection. MIF expression is upregulated during DENV infection. Blocking MIF function by a MIF inhibitor (ISO-1) or MIF antibodies or its signal transduction by U0126 (Erk inhibitor), Ly294002 (PI3K inhibitor), or SP600125 (JNK inhibitor) may prevent MIF-induced permeability. In addition, MIF-induced autophagy may enhance DENV replication; therefore, blocking autophagy by NAC (ROS scavenger), 3-MA (autophagy inhibitor), or a MIF inhibitor (ISO-1) may reduce DENV replication. In addition, MIF induces the upregulation of ICAM-1 and LFA-1 expression, which may influence leukocyte recruitment. Finally, TM expression induced by MIF may activate protein C and inhibit thrombin formation. These effects of MIF can be blocked by its inhibitor or an antibody.