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

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.

Keywords:

• ATG7
• autophagy
• host genetics
• innate immunity
• poliomyelitis
• poliovirus
• neuronal-like cells
• whole exome sequencing

Disclosure statement

The authors declare that they have no competing interests.

Acknowledgments

We wish to thank the patient for participating in the study and Polio Denmark for the collaboration. In addition, we thank Bente Ladegaard and Kirsten Stadel Pedersen for technical assistance in the laboratory. Cell sorting was performed at the FACS Core Facility, Aarhus University, Denmark.

THM received funding from Aarhus University Research Fund (AUFF-E-215-FLS-8-66), the Danish Council for Independent Research-Medical Sciences (# 4004-00047B), The Novo Nordisk Foundation (NNF15OC0017462) and The Lundbeck Foundation (R268-2016-3927). SRP was funded by the European Research Council (ERC-AdG ENVISION; 786602), the Novo Nordisk Foundation (NNF18OC0030274) and the Lundbeck Foundation (R198-2015-171). The project was funded by A.P. Møller og Hustru Chastine Mc-Kinney Møller.

List of abbreviations

AWOL: autophagosome-mediated exit without lysis; AD: adenylation domain; ATG: autophagy related; CADD: combined annotation-dependent depletion; CRISPR: clustered regularly interspaced short palindromic repeats; EMCV: encephalomyocarditis virus; GDI: gene damage index; gnomAD: genome aggregation database; HSV-I; herpes simplex virus type 1; IFN, interferon; LDH: lactate dehydrogenase; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; MdMs: monocyte-derived macrophages; PBMC: peripheral blood mononuclear cell; PPM: paralytic poliomyelitis; PV: poliovirus; WES: whole-exome sequencing.

Ethics

The project was approved by the Danish National Committee in Health Research Ethics (#1-10-72-66-16) and the Danish Data protection Agency (#1-16-02-216-16) in accordance with the ethical standards of the Helsinki Declaration. Written informed consent was obtained from all study participants.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the Aarhus Universitets Forskningsfond [AUFF-E-215-FLS-8-66]; European Research Council [ERC-AdG ENVISION; 786602]; Lundbeckfonden [R268-2016-3927]; Lundbeckfonden [R198-2015-171]; Novo Nordisk Fonden [NNF18OC0030274]; Sundhed og Sygdom, Det Frie Forskningsråd [4004-00047B].