Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections.

IF 5.4 3区 材料科学 Q2 CHEMISTRY, PHYSICAL
ACS Applied Energy Materials Pub Date : 2023-01-01 Epub Date: 2022-06-23 DOI:10.1159/000525291
Divya Narayanan, Nagaraj Moily, Hayley A McQuilten, Katherine Kedzierska, Jason M Mackenzie, Lukasz Kedzierski, John K Fazakerley
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引用次数: 1

Abstract

Virus infections of the central nervous system (CNS) cause important diseases of humans and animals. As in other tissues, innate antiviral responses mediated by type I interferons (IFNs) are crucially important in controlling CNS virus infections. The maturity of neuronal populations is an established critical factor determining the outcome of CNS virus infection. Using primary cultures of mouse cortical neurons, we investigated the relationships between neuronal maturation, type I IFN responses, and the outcome of Semliki Forest virus infection. The virus replicated better, infected more cells, and produced higher titres of infectious viruses in immature neurons. Complete transcriptome analysis demonstrated that resting immature neurons have low transcriptional competence to mount antiviral responses. They had no detectable transcription of the genes Ddx58 and Ifih1, which encode key RNA virus cytoplasmic sensors RIG-I and MDA5, and very low expression of genes encoding key regulators of associated signalling pathways. Upon infection, immature neurons failed to mount an antiviral response as evidenced by their failure to produce chemokines, IFNs, and other cytokines. Treatment of immature neurons with exogenous IFNβ prior to infection resulted in antiviral responses and lower levels of virus replication and infectious virus production. In contrast, resting mature neurons generated a robust antiviral response. This was augmented by pretreatment with IFNβ. Infection of mature neurons derived from IFNAR-/- mice did not make an antiviral response and replicated virus to high levels.

未成熟脑皮质神经元激活抗病毒防御和控制RNA病毒感染的转录能力低。
病毒感染中枢神经系统(CNS)导致人类和动物的重要疾病。与其他组织一样,I型干扰素(ifn)介导的先天抗病毒反应在控制中枢神经系统病毒感染中至关重要。神经细胞群体的成熟度是确定中枢神经系统病毒感染结果的关键因素。利用小鼠皮质神经元原代培养,我们研究了神经元成熟、I型IFN反应和塞姆利基森林病毒感染结果之间的关系。这种病毒复制得更好,感染了更多的细胞,并在未成熟的神经元中产生了更高滴度的传染性病毒。完整的转录组分析表明,静息的未成熟神经元具有较低的转录能力来产生抗病毒反应。它们没有检测到编码关键RNA病毒细胞质传感器RIG-I和MDA5的基因Ddx58和Ifih1的转录,编码相关信号通路关键调节因子的基因表达非常低。感染后,未成熟的神经元不能产生趋化因子、ifn和其他细胞因子,这证明了它们不能产生抗病毒反应。在感染前用外源性IFNβ处理未成熟神经元导致抗病毒反应和较低水平的病毒复制和感染性病毒产生。相比之下,静止的成熟神经元产生了强大的抗病毒反应。IFNβ预处理增强了这一点。来自IFNAR-/-小鼠的成熟神经元的感染不会产生抗病毒反应,并复制高水平的病毒。
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来源期刊
ACS Applied Energy Materials
ACS Applied Energy Materials Materials Science-Materials Chemistry
CiteScore
10.30
自引率
6.20%
发文量
1368
期刊介绍: ACS Applied Energy Materials is an interdisciplinary journal publishing original research covering all aspects of materials, engineering, chemistry, physics and biology relevant to energy conversion and storage. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important energy applications.
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