Abstract
Dengue virus (DENV) infection is the most prevalent mosquito-borne viral infection and can lead to severe dengue hemorrhagic fever (DHF) and even life-threatening dengue shock syndrome (DSS). Although the cytokine storm has been revealed as a critical factor in dengue disease, the limited understanding of dengue immunopathogenesis hinders the development of effective treatments. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that mediates diverse immune responses, and the serum level of MIF positively correlates with disease severity in patients with dengue. MIF is involved in DENV replication and many pathological changes, such as vascular leakage, during DENV infection. In this paper, the pathogenic roles of MIF and the regulation of MIF secretion during DENV infection are reviewed. Furthermore, whether MIF is a potential therapeutic target against DENV infection is also discussed.
Highlights
Dengue virus (DENV) infection is the most widespread mosquito-borne viral infection in the tropics and subtropics
The release of migration inhibitory factor (MIF) from neutrophils may induce neutrophil extracellular traps (NETs) formation and inflammation in DENV infection, which contributes to dengue pathogenesis
Since no obvious lactate dehydrogenase (LDH) release nor a significant increase in MIF mRNA occurred during this period of time, these results suggest that the first wave of MIF secretion was caused by the release of MIF from intracellular pools, and this secretion is independent of MIF gene transcription and cell death [50]
Summary
Dengue virus (DENV) infection is the most widespread mosquito-borne viral infection in the tropics and subtropics. The antibody-dependent enhancement (ADE) theory of dengue pathogenesis was first proposed by Halstead in 1977 [9] to explain the phenomenon in which secondary infection with different serotypes of DENV may cause more severe disease development. According to the ADE theory, antibodies (Abs) stimulated by the primary infection can only partially bind to different serotypes of DENV (heterotypic DENV virion) and cannot fully neutralize infection Instead, these subneutralizing Abs facilitate viral entry by binding with Fc receptors on immune cells, which results in robust infection. At the time of plasma leakage, elevated levels of permeability-enhancing factors, tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor-A (VEGFA) are found in severe dengue patients and contribute to three main pathological features: plasma leakage, hemorrhage and coagulopathy [24,25] It is unclear which proinflammatory cytokines dominate the cytokine storm upon DENV infection. In this review, we will focus on the pathogenic roles of MIF during DENV infection and discuss whether it can be a therapeutic target against DENV infection
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