Donátová Karin, Mladá Miriam, Lopušná Katarína, Baran Filip, Betáková Tatiana
Department of Microbiology and Virology, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia.
Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia.
Int J Mol Sci. 2024 Feb 20;25(5):2460. doi: 10.3390/ijms25052460.
Influenza type A virus (IAV) infection is a major cause of morbidity and mortality during influenza epidemics. Recently, a specific link between IAV infection and neurodegenerative disease progression has been established. The non-structural NS1 protein of IAV regulates viral replication during infection and antagonizes host antiviral responses, contributing to influenza virulence. In the present study, we have prepared a mouse lung-to-lung adapted to the NS1-truncated virus (NS80ad). Transcriptome analysis of the gene expression in the lungs revealed that infection with wild-type A/WSN/33 (WSN), NS80, and NS80ad viruses resulted in different regulation of genes involved in signaling pathways associated with the cell proliferation, inflammatory response, and development of neurodegenerative diseases. NS1 protein did not influence the genes involved in the RIG-I-like receptor signaling pathway in the brains. Lethal infection with IAVs dysregulated expression of proteins associated with the development of neurodegenerative diseases (CX3CL1/Fractalkine, Coagulation factor III, and CD105/Endoglin, CD54/ICAM-1, insulin-like growth factor-binding protein (IGFBP)-2, IGFBP-5, IGFBP-6, chitinase 3-like 1 (CHI3L1), Myeloperoxidase (MPO), Osteopontin (OPN), cystatin C, and LDL R). Transcription of GATA3 mRNA was decreased, and expression of MPO was inhibited in the brain infected with NS80 and NS80ad viruses. In addition, the truncation of NS1 protein led to reduced expression of IGFBP-2, CHI3L1, MPO, and LDL-R proteins in the brains. Our results indicate that the influenza virus influences the expression of proteins involved in brain function, and this might occur mostly through the NS1 protein. These findings suggest that the abovementioned proteins represent a promising target for the development of potentially effective immunotherapy against neurodegeneration.
甲型流感病毒（IAV）感染是流感流行期间发病和死亡的主要原因。最近，IAV感染与神经退行性疾病进展之间建立了特定联系。IAV的非结构NS1蛋白在感染期间调节病毒复制并拮抗宿主抗病毒反应，从而导致流感病毒的毒力。在本研究中，我们制备了一种适应NS1截短病毒（NS80ad）的小鼠肺传代病毒。对肺组织中基因表达的转录组分析表明，野生型A/WSN/33（WSN）、NS80和NS80ad病毒感染导致参与细胞增殖、炎症反应和神经退行性疾病发展的信号通路相关基因的不同调控。NS1蛋白不影响大脑中参与RIG-I样受体信号通路的基因。IAV的致死性感染使与神经退行性疾病发展相关的蛋白质（CX3CL1/趋化因子、凝血因子III、CD105/内皮糖蛋白、CD54/细胞间黏附分子-1、胰岛素样生长因子结合蛋白（IGFBP）-2、IGFBP-5、IGFBP-6、几丁质酶3样1（CHI3L1）、髓过氧化物酶（MPO）、骨桥蛋白（OPN）、胱抑素C和低密度脂蛋白受体（LDL R））的表达失调。在感染NS80和NS80ad病毒的大脑中，GATA3 mRNA的转录减少，MPO的表达受到抑制。此外，NS1蛋白的截短导致大脑中IGFBP-2、CHI3L1、MPO和LDL-R蛋白的表达降低。我们的结果表明，流感病毒影响参与脑功能的蛋白质的表达，这可能主要通过NS1蛋白发生。这些发现表明，上述蛋白质是开发针对神经退行性变的潜在有效免疫疗法的有希望的靶点。
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