Transcriptome Study On Influenza A Virus In Association With Neuroinflammation And Neurodegeneration Disorders

Neurodegenerative disorders are incurable diseases of the central nervous system(CNS)caused by nerve cell death or injuries,such as Alzheimer’s and Parkinson’s diseases.Interestingly,one of its recent suspicious causative agents is the influenza virus,commonly known as a respiratory virus infection.The CNS has a specific defense mechanism against pathogens structured by cerebral microvasculature lined with brain endothelial cells to form the blood-brain barrier(BBB).In order to investigate the response of the human brain microvascular endothelial cells(h BMECs)to the influenza A virus,the primary human cell line h BMECs were infected with the influenza A/WSN/33(H1N1)virus.The influenza virus nucleoprotein(NP)gene expression and translated protein were detected via RT-q PCR and western blotting.At the same time,the immunofluorescence showed the differential distribution of the viral NP within the cells.RNAseq was performed following infection of h BMECs with H1N1 at 12 hpi and BALB/c mouse brain tissue with H5N6 at 3 dpi,and gene expression and disease pathways were analyzed.It was demonstrated that h BMECs is highly sensitive to influenza A virus infection.The immunofluorescence revealed an accumulation of the viral NP in the cell nucleus and a colocalization between viral NP and actin cytoskeleton at 12 hpi.The h BMECs effectively activated the pattern recognition receptors(PRRs)and RIG-I-like receptor signalings of innate immune defense.A storm of proinflammatory cytokines was induced with the up-regulation of several interferon-stimulated genes,such as IFN-β,IFN-λ,ISG15,CXCL11,CXCL3,and IL-6,etc.Besides,h BMECs exhibited multiple mitochondrial complex genes disruption with a similar pattern to Alzheimer’s disease patients.The differentially expressed genes of the BALB/c mice brain tissue predict a manifestation of CNS disorders.Significant dysfunction to genes processing in the CNS development and glutamatergic synapse functions was observed.However,the neuroactive ligand-receptor interaction pathway shows significant up-regulation for the h BMECs and mice brain tissue following the influenza A virus infection.En masse,these data provide evidence for the role played by h BMECs to illustrate the potential response of BBB to the influenza A virus and the subsequent aggravation of neurodegenerative disorders taking place in the brain.