Brain transcriptomics reveals features of the host response after dengue virus type I infection induced central nervous system injury in AGB6 mice

Abstract

Dengue viruses are the causative agents of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, which are mainly transmitted by Aedes aegypti and Aedes albopictus mosquitoes, and cost billions of dollars annually in medical and mosquito control. It is estimated that up to 20% of dengue virus infections affect the brain. The incidence of DENV infection of the nervous system is increasing, suggesting that more people are at risk for neurological complications of the infection. Currently, understanding the pathogenic mechanisms of dengue virus infection of the nervous system is hampered by the lack of suitable small animal models. Here, we analyzed the pathogenicity of dengue virus in type I and type interferon receptor-deficient mice by intraperitoneal inoculation of DENV-I. Infected mice showed such neurological symptoms as opisthotonus, hunching, ataxia, and paralysis of one or both hind limbs. Viremia can be detected 3 days after infection. The virus showed evident brain tropism post-inoculation and viral loads peaked at 14 days post-inoculation in infected mice brain. Significant histopathologic changes were observed in brain tissue (hippocampal region and cerebral cortex). Immunohistochemistry and fluorescence showed clear fluorescent signals. Hematological analysis showed hemorrhage and hemoconcentration in DENV-I infected mice. Subsequently, brain tissue transcriptome sequencing was performed to assess host response characteristics in DENV-I infected AGB6 mice. Functional enrichment analysis and analysis of significantly differentially expressed genes (DEGs) were used to identify the key molecular mechanisms of brain tissue injury. Transcriptional patterns in brain tissue suggest that aberrant expression of pro-inflammatory cytokines induces antiviral responses to dengue virus and tissue damage. Combined with the KEGG results, it was hypothesized that the probable cause of the neurological damage affecting the neurological system and hindlimb paralysis was the marked enrichment of upregulated DEGs in the cytokine-cytokine receptor interaction signaling pathway. Screening of hub genes and their characterization by qPCR and ELISA, it was hypothesized that IL-6 and IFN-{gamma} might be the key factors in dengue virus-induced neurological manifestations.