ABSTRACT

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 in ATG7, 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.

摘要

麻痹性脊髓灰质炎是脊髓灰质炎病毒 (PV) 感染后的一种罕见疾病表现。疾病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人类疾病结果发展的可能贡献。我们确定了一名患有ATG7变异的患者，巨自噬/自噬通路中的重要调控基因。PV 感染并没有诱导显着的 I 型干扰素反应，而是激活了神经元样细胞中的自噬，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有关。ATG7 的缺乏阻止了对神经元样细胞中感染的控制，并且用野生型 ATG7 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 ATG7 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未被重视的抗病毒效应物。