Essential role of autophagy in restricting poliovirus infection revealed by identification of an ATG7 defect in a poliomyelitis patient
Essential role of autophagy in restricting poliovirus infection revealed by identification of an ATG7 defect in a poliomyelitis patient
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DOI：
10.1080/15548627.2020.1831800
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发表时间：
2020-10-21
期刊：
影响因子：
13.3
通讯作者：
Mogensen, Trine H.
中科院分区：
文献类型：
--
作者：
Brinck Andersen, Nanna-Sophie;Jorgensen, Sofie Eg;Mogensen, Trine H.
麻痹性脊髓灰质炎是脊髓灰质炎病毒（PV）感染后的罕见疾病表现。疾病的决定因素在很大程度上仍然未知。我们使用全外显子组测序来揭示宿主遗传学对脊髓灰质炎患者疾病结局发展的可能贡献。我们鉴定了一个ATG 7变异的患者，ATG 7是巨自噬/自噬途径中的一个重要调控基因。PV感染并没有诱导显著的I型干扰素应答，而是激活了神经元样细胞的自噬，这对于病毒控制至关重要。重要的是，病毒诱导的自噬在患者成纤维细胞中受损，并与感染后病毒负荷增加和细胞死亡增加相关。缺乏ATG 7阻止了神经元样细胞中的感染控制，并且用野生型ATG 7重建患者细胞重新建立了自噬介导的感染控制。总的来说，这些数据表明，ATG 7缺陷有助于宿主对PV感染的易感性，并提出自噬作为人类病毒感染中不受重视的抗病毒效应子。
Paralytic poliomyelitis is a rare disease manifestation following poliovirus (PV) infection. The disease determinants remain largely unknown. We used whole exome sequencing to uncover possible contributions of host genetics to the development of disease outcome in humans with poliomyelitis. We identified a patient with a variant inATG7, an important regulatory gene in the macroautophagy/autophagy pathway. PV infection did not induce a prominent type I interferon response, but rather activated autophagy in neuronal-like cells, and this was essential for viral control. Importantly, virus-induced autophagy was impaired in patient fibroblasts and associated with increased viral burden and enhanced cell death following infection. Lack of ATG7 prevented control of infection in neuronal-like cells, and reconstitution of patient cells with wild-type ATG7 reestablished autophagy-mediated control of infection. Collectively, these data suggest that ATG7 defect contributes to host susceptibility to PV infection and propose autophagy as an unappreciated antiviral effector in viral infection in humans.