Abstract
Infection with flaviviruses causes mild to severe diseases, including viral hemorrhagic fever, vascular shock syndrome, and viral encephalitis. Several animal models explore the pathogenesis of viral encephalitis, as shown by neuron destruction due to neurotoxicity after viral infection. While neuronal cells are injuries caused by inflammatory cytokine production following microglial/macrophage activation, the blockade of inflammatory cytokines can reduce neurotoxicity to improve the survival rate. This study investigated the involvement of macrophage phenotypes in facilitating CNS inflammation and neurotoxicity during flavivirus infection, including the Japanese encephalitis virus, dengue virus (DENV), and Zika virus. Mice infected with different flaviviruses presented encephalitis-like symptoms, including limbic seizure and paralysis. Histology indicated that brain lesions were identified in the hippocampus and surrounded by mononuclear cells. In those regions, both the infiltrated macrophages and resident microglia were significantly increased. RNA-seq analysis showed the gene profile shifting toward type 1 macrophage (M1) polarization, while M1 markers validated this phenomenon. Pharmacologically blocking C-C chemokine receptor 2 and tumor necrosis factor-α partly retarded DENV-induced M1 polarization. In summary, flavivirus infection, such as JEV and DENV, promoted type 1 macrophage polarization in the brain associated with encephalitic severity.
Highlights
Flavivirus, a genus of arthropod-borne virus that belongs to the Flaviviridae family, contains almost 73 viruses
This study first revealed that dengue virus (DENV) infection could induce viral encephalitis by causing macrophage infiltration in the brain, the development of M1 macrophage polarization, and its related inflammatory responses
What is puzzling is that Zika virus (ZIKV) did not cause virus replication in the brain or induce severe encephalitis-like symptoms compared with Japanese encephalitis virus (JEV) or DENV
Summary
Flavivirus, a genus of arthropod-borne virus that belongs to the Flaviviridae family, contains almost 73 viruses. Flaviviruses, such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV), can be transmitted through mosquitoes and cause one million infections annually [1]. Several DENV-infected rodent models show viral protein expression in the brain accompanied by immune activation [11,12,13,14]. Pharmacological blockade of microglia-derived tumor necrosis factor (TNF)-α expression further shows cytoprotection from DENV-induced neurotoxicity [17]. These studies suggest that microglial activation may play a pathogenic role in CNS inflammation during viral infection. Microglial depletion does not reduce disease symptoms or mortality, but instead promotes disease progression and the onset of mortality, indicating that microglial activation is essential for the CNS immune defense against viral infection [12,18]
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