Altered gene expression in human brain microvascular endothelial cells in response to the infection of influenza H1N1 virus

Abstract

Influenza viruses not only cause respiratory illness, but also have been reported to elicit neurological manifestations following acute viral infection. The central nervous system (CNS) has a specific defense mechanism against pathogens structured by cerebral microvasculature lined with brain endothelial cells to form the blood–brain barrier (BBB). To investigate the response of human brain microvascular endothelial cells (hBMECs) to the Influenza A virus (IAV), we inoculated the cells with the A/WSN/33 (H1N1) virus. We then conducted an RNAseq experiment to determine the changes in gene expression levels and the activated disease pathways following infection. The analysis revealed an effective activation of the innate immune defense by inducing the pattern recognition receptors (PRRs). Along with the production of proinflammatory cytokines, we detected an upregulation of interferons and interferon-stimulated genes, such as IFN-β/λ, ISG15, CXCL11, CXCL3 and IL-6, etc. Moreover, infected hBMECs exhibited a disruption in the cytoskeletal structure both on the transcriptomic and cytological levels. The RNAseq analysis showed different pathways and candidate genes associated with the neuroactive ligand-receptor interaction, neuroinflammation, and neurodegenerative diseases, together with a predicted activation of the neuroglia. Likewise, some genes linked with the mitochondrial structure and function displayed a significantly altered expression. En masse, this data supports that hBMECs could be infected by the IAV, which induces the innate and inflammatory immune response. The results suggest that the influenza virus infection could potentially induce a subsequent aggravation of neurological disorders.

Risk factors for death associated with severe influenza in children and the impact of the COVID-19 pandemic on clinical characteristics

“…The disease has rapid onset and progression, with a high mortality rate in severe patients and varying degrees of neurological sequelae in survivors ( 22 ). However, the pathogenesis of ANE is still unclear, and studies have shown an association with high levels of cytokines in plasma and cerebrospinal fluid, particularly interleukin (IL)6, tumor necrosis factor (TNF)alpha, leading to a storm of cellular inflammatory factors that induce innate and inflammatory immune responses ( 23 , 24 ). In Japan, ANE had the highest incidence in the 0–4 age group from 2004 to 2009, but a new change occurred during influenza A(H1N1) from 2009 to 2010, with the highest incidence in the 5–9 years age group.…”

Type I/type III IFN and related factors regulate JEV infection and BBB endothelial integrity

“…Intriguingly, to extend the period of viral replication, JEV may interfere with the apoptotic pathway of transfected human brain microvascular endothelial cells (hBMECs) [ 8 ]. Aside from their well-characterized barrier function, BMECs can be immune activated to mount effective IFN induction and IFN-stimulated gene (ISG) expression as a response to viral infections, including human immunodeficiency virus (HIV), Zika virus (ZIKV), and influenza virus [ 11 – 13 ]. In restricting WNV transit, IFN-λ signaling promotes BMEC barrier tightening [ 14 ].…”