Zika virus-induced TNF-α signaling dysregulates expression of neurologic genes associated with psychiatric disorders.
Zika virus-induced TNF-α signaling dysregulates expression of neurologic genes associated with psychiatric disorders.
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DOI：
10.1186/s12974-022-02460-8
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发表时间：
2022-04-24
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
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作者：
寨卡病毒（ZIKV）是一种引起全球关注的新型黄病毒。中枢神经系统的ZIKV感染与多种临床综合征有关，包括胎儿的小头畸形和成人中罕见但严重的神经系统疾病。然而，ZIKV在明显轻度或亚临床感染后影响脑生理学和宿主行为的潜力尚不清楚。此外，尽管在从神经侵入性病毒感染恢复后认知功能的缺陷被充分记录，但ZIKV对其他宿主行为领域的潜在影响尚未被彻底探索。我们使用转录组学分析，包括无偏基因本体富集分析，来评估ZIKV感染对原代皮层神经元培养物中基因表达的影响。这些研究扩展了基因表达和炎症细胞因子信号传导的分子生物学分析。使用免疫活性宿主中建立的ZIKV感染的体内模型进一步证实了体外观察结果。ZIKV感染后原代神经元培养物的转录组学分析揭示了与主要精神障碍（如双相情感障碍和精神分裂症）相关的关键基因的表达改变。基因本体富集分析还揭示了与基本神经生物学过程相关的基因表达的显著变化，包括神经元发育、神经传递等。使用几种ZIKV感染的免疫活性小鼠模型，在体内脑中也观察到神经基因表达的这些改变。机制研究确定通过TNFR 1的TNF-α信号传导是控制ZIKV诱导的神经基因表达变化的主要调节机制。我们的研究揭示了对ZIKV感染的细胞固有先天免疫应答深刻地塑造了神经元转录谱，突出了进一步探索ZIKV感染和紊乱的宿主行为状态之间的关联的需要。在线版本包含补充材料，可通过10.1186/s12974-022-02460-8获取。
Zika virus (ZIKV) is an emerging flavivirus of global concern. ZIKV infection of the central nervous system has been linked to a variety of clinical syndromes, including microcephaly in fetuses and rare but serious neurologic disease in adults. However, the potential for ZIKV to influence brain physiology and host behavior following apparently mild or subclinical infection is less well understood. Furthermore, though deficits in cognitive function are well-documented after recovery from neuroinvasive viral infection, the potential impact of ZIKV on other host behavioral domains has not been thoroughly explored. We used transcriptomic profiling, including unbiased gene ontology enrichment analysis, to assess the impact of ZIKV infection on gene expression in primary cortical neuron cultures. These studies were extended with molecular biological analysis of gene expression and inflammatory cytokine signaling. In vitro observations were further confirmed using established in vivo models of ZIKV infection in immunocompetent hosts. Transcriptomic profiling of primary neuron cultures following ZIKV infection revealed altered expression of key genes associated with major psychiatric disorders, such as bipolar disorder and schizophrenia. Gene ontology enrichment analysis also revealed significant changes in gene expression associated with fundamental neurobiological processes, including neuronal development, neurotransmission, and others. These alterations to neurologic gene expression were also observed in the brain in vivo using several immunocompetent mouse models of ZIKV infection. Mechanistic studies identified TNF-α signaling via TNFR1 as a major regulatory mechanism controlling ZIKV-induced changes to neurologic gene expression. Our studies reveal that cell-intrinsic innate immune responses to ZIKV infection profoundly shape neuronal transcriptional profiles, highlighting the need to further explore associations between ZIKV infection and disordered host behavioral states. The online version contains supplementary material available at 10.1186/s12974-022-02460-8.
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