Essential role of autophagy in restricting poliovirus infection revealed by identification of an ATG7 defect in a poliomyelitis patient

• Published in: Autophagy Vol. 17; no. 9; pp. 2449 - 2464
• Main Authors: Brinck Andersen, Nanna-Sophie, Jørgensen, Sofie Eg, Skipper, Kristian Alsbjerg, Larsen, Simon Müller, Heinz, Johanna, Thomsen, Michelle Mølgaard, Farahani, Ensieh, Cai, Yujia, Hait, Alon Schneider, Kay, Lise, Giehm Mikkelsen, Jacob, Høgsbjerg Schleimann, Mariane, Thomsen, Martin Kristian, Paludan, Søren R., Mogensen, Trine H.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.09.2021
• Subjects: ATG7; autophagy; Autophagy - genetics; Autophagy-Related Protein 7 - genetics; host genetics; Humans; innate immunity; Interferon Type I; neuronal-like cells; Neurons; poliomyelitis; Poliomyelitis - genetics; Poliomyelitis - prevention & control; poliovirus; Poliovirus - genetics; Research Paper; whole exome sequencing; autophagy; innate immunity; neuronal-like cells; poliomyelitis; host genetics; ATG7; whole exome sequencing; poliovirus
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2020.1831800

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.