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

Nanna Sophie Brinck Andersen, Sofie Eg Jørgensen, Kristian Alsbjerg Skipper, Simon Müller Larsen, Johanna Heinz, Michelle Mølgaard Thomsen, Ensieh Farahani, Yujia Cai, Alon Schneider Hait, Lise Kay, Jacob Giehm Mikkelsen, Mariane Høgsbjerg Schleimann, Martin Kristian Thomsen, Søren R. Paludan, Trine H. Mogensen*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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.

Original languageEnglish
JournalAutophagy
Volume17
Issue9
Pages (from-to)2449-2464
Number of pages16
ISSN1554-8627
DOIs
Publication statusPublished - Sept 2021

Keywords

  • ATG7
  • autophagy
  • host genetics
  • innate immunity
  • neuronal-like cells
  • poliomyelitis
  • poliovirus
  • whole exome sequencing
  • IMMUNITY
  • DENDRITIC CELLS
  • RECEPTOR
  • MACROAUTOPHAGY
  • INDUCTION
  • LESSONS
  • PROTECTS
  • PATHOGENESIS
  • PATHOGENICITY
  • MUTATION

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