Polarization of Type 1 Macrophages Is Associated with the Severity of Viral Encephalitis Caused by Japanese Encephalitis Virus and Dengue Virus

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.

The role of glial cells in Zika virus‐induced neurodegeneration

“…Moreover, T cell‐derived interferon‐γ (IFN‐γ) signaling is required for microglial activation and seems to be involved in ZIKV post‐infection cognitive sequelae by eliminating pre‐ and post‐synaptic terminals (Garber et al, 2019). Flaviviruses can also promote type 1 macrophage polarization in the brain, which is associated with encephalitic severity (Jhan et al, 2021). Other experimental data from the infected brain of mice indicate that ZIKV with high pathogenicity may induce sustained activation of the immune system, including macrophage activation, leading to nerve tissue damage (Shang et al, 2022).…”

Deep Proteomics Network and Machine Learning Analysis of Human Cerebrospinal Fluid in Japanese Encephalitis Virus Infection

“…To date, to our knowledge, two studies have utilized unbiased techniques to examine the CSF proteome in human patients with confirmed JEV infection; while they demonstrate the feasibility of the methods, the patients were not confirmed by seroneutralization and included relatively small numbers of patients (10 and 26 JE patients). , There have been a handful of studies utilizing ELISA methods to target specific proteins; however, these rarely used power calculations in their experimental design, nor did they include adequate controls. − Analysis of the transcriptome and proteome in animal models − and cell culture ,,− have been performed; however, the comparability to human CSF and comparison with other neurological infections is limited. Furthermore, mRNA expression does not directly correlate with that of the corresponding protein …”

Deep proteomics network and machine learning analysis of human cerebrospinal fluid in Japanese encephalitis virus infection

“…There have been a handful of studies utilizing ELISA methods to target specific proteins, however these rarely used power calculations in their experimental design, nor did they include adequate controls (48)(49)(50)(51)(52)(53). Analysis of the transcriptome and proteome in animal models (54)(55)(56)(57)(58) and cell culture (48,54,(59)(60)(61)(62)(63)(64) have been performed, however the comparability to human CSF and comparison with other neurological infections is limited. Furthermore, mRNA expression does not directly correlate with that of the corresponding protein (65).…”