Enterovirus-A71 preferentially infects and replicates in human motor neurons, inducing neurodegeneration by ferroptosis.

IF 8.4 2区 医学 Q1 IMMUNOLOGY Emerging Microbes & Infections Pub Date : 2024-12-01 Epub Date: 2024-07-25 DOI:10.1080/22221751.2024.2382235
Wai Hon Chooi, Winanto, Yingying Zeng, Cheryl Yi-Pin Lee, Ze Qin Lim, Pradeep Gautam, Justin Jang Hann Chu, Yuin-Han Loh, Sylvie Alonso, Shi-Yan Ng
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Abstract

Enterovirus A71 (EV-A71) causes Hand, Foot, and Mouth Disease and has been clinically associated with neurological complications. However, there is a lack of relevant models to elucidate the neuropathology of EV-A71 and its mechanism, as the current models mainly utilize animal models or immortalized cell lines. In this study, we established a human motor neuron model for EV-A71 infection. Single cell transcriptomics of a mixed neuronal population reveal higher viral RNA load in motor neurons, suggesting higher infectivity and replication of EV-A71 in motor neurons. The elevated RNA load in motor neurons correlates with the downregulation of ferritin-encoding genes. Subsequent analysis confirms that neurons infected with EV-A71 undergo ferroptosis, as evidenced by increased levels of labile Fe2+ and peroxidated lipids. Notably, the Fe2+ chelator Deferoxamine improves mitochondrial function and promotes survival of motor neurons by 40% after EV-A71 infection. These findings deepen understanding of the molecular pathogenesis of EV-A71 infection, providing insights which suggest that improving mitochondrial respiration and inhibition of ferroptosis can mitigate the impact of EV-A71 infection in the central nervous system.

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肠道病毒-A71 优先感染并复制人类运动神经元,通过铁突变诱导神经变性。
肠道病毒 A71(EV-A71)可导致手足口病,并在临床上与神经系统并发症有关。然而,由于目前的模型主要利用动物模型或永生化细胞系,因此缺乏相关模型来阐明 EV-A71 的神经病理学及其机制。在这项研究中,我们建立了一个人类运动神经元感染 EV-A71 的模型。混合神经元群体的单细胞转录组学显示,运动神经元中的病毒 RNA 量更高,这表明 EV-A71 在运动神经元中具有更高的感染性和复制性。运动神经元中 RNA 负荷的升高与铁蛋白编码基因的下调有关。随后的分析证实,感染了 EV-A71 的神经元会发生铁变态反应,表现为可溶性 Fe2+ 和过氧化脂质水平升高。值得注意的是,Fe2+螯合剂去铁胺能改善线粒体功能,并在EV-A71感染后将运动神经元的存活率提高40%。这些发现加深了人们对EV-A71感染的分子发病机制的了解,并提供了一些见解,表明改善线粒体呼吸和抑制铁变态反应可减轻EV-A71感染对中枢神经系统的影响。
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来源期刊
Emerging Microbes & Infections
Emerging Microbes & Infections IMMUNOLOGY-MICROBIOLOGY
CiteScore
26.20
自引率
2.30%
发文量
276
审稿时长
20 weeks
期刊介绍: Emerging Microbes & Infections is a peer-reviewed, open-access journal dedicated to publishing research at the intersection of emerging immunology and microbiology viruses. The journal's mission is to share information on microbes and infections, particularly those gaining significance in both biological and clinical realms due to increased pathogenic frequency. Emerging Microbes & Infections is committed to bridging the scientific gap between developed and developing countries. This journal addresses topics of critical biological and clinical importance, including but not limited to: - Epidemic surveillance - Clinical manifestations - Diagnosis and management - Cellular and molecular pathogenesis - Innate and acquired immune responses between emerging microbes and their hosts - Drug discovery - Vaccine development research Emerging Microbes & Infections invites submissions of original research articles, review articles, letters, and commentaries, fostering a platform for the dissemination of impactful research in the field.
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