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

doi:10.1080/15548627.2020.1831800

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 newspaper › Journal article › Research › peer-review

9 Citations (Scopus)

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 language	English
Journal	Autophagy
Volume	17
Issue	9
Pages (from-to)	2449-2464
Number of pages	16
ISSN	1554-8627
DOIs	https://doi.org/10.1080/15548627.2020.1831800
Publication status	Published - 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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10.1080/15548627.2020.1831800

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496727/pdf/KAUP_17_1831800.pdf

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Brinck Andersen, N. S., Jørgensen, S. E., Skipper, K. A., Larsen, S. M., Heinz, J., Thomsen, M. M., Farahani, E., Cai, Y., Hait, A. S., Kay, L., Giehm Mikkelsen, J., Høgsbjerg Schleimann, M., Thomsen, M. K., Paludan, S. R., & Mogensen, T. H. (2021). Essential role of autophagy in restricting poliovirus infection revealed by identification of an ATG7 defect in a poliomyelitis patient. Autophagy, 17(9), 2449-2464. https://doi.org/10.1080/15548627.2020.1831800

@article{a498e2fbf7a94eb38c46a0a229da79ab,

title = "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, neuronal-like cells, poliomyelitis, poliovirus, whole exome sequencing, IMMUNITY, DENDRITIC CELLS, RECEPTOR, MACROAUTOPHAGY, INDUCTION, LESSONS, PROTECTS, PATHOGENESIS, PATHOGENICITY, MUTATION",

author = "{Brinck Andersen}, {Nanna Sophie} and J{\o}rgensen, {Sofie Eg} and Skipper, {Kristian Alsbjerg} and Larsen, {Simon M{\"u}ller} and Johanna Heinz and Thomsen, {Michelle M{\o}lgaard} and Ensieh Farahani and Yujia Cai and Hait, {Alon Schneider} and Lise Kay and {Giehm Mikkelsen}, Jacob and {H{\o}gsbjerg Schleimann}, Mariane and Thomsen, {Martin Kristian} and Paludan, {S{\o}ren R.} and Mogensen, {Trine H.}",

year = "2021",

month = sep,

doi = "10.1080/15548627.2020.1831800",

language = "English",

volume = "17",

pages = "2449--2464",

journal = "Autophagy",

issn = "1554-8627",

publisher = "Taylor and Francis Ltd.",

number = "9",

}

Brinck Andersen, NS, Jørgensen, SE , Skipper, KA, Larsen, SM, Heinz, J, Thomsen, MM, Farahani, E, Cai, Y, Hait, AS, Kay, L, Giehm Mikkelsen, J , Høgsbjerg Schleimann, M , Thomsen, MK , Paludan, SR & Mogensen, TH 2021, 'Essential role of autophagy in restricting poliovirus infection revealed by identification of an ATG7 defect in a poliomyelitis patient', Autophagy, vol. 17, no. 9, pp. 2449-2464. https://doi.org/10.1080/15548627.2020.1831800

Essential role of autophagy in restricting poliovirus infection revealed by identification of an ATG7 defect in a poliomyelitis patient. / Brinck Andersen, Nanna Sophie; Jørgensen, Sofie Eg ; Skipper, Kristian Alsbjerg et al.
In: Autophagy, Vol. 17, No. 9, 09.2021, p. 2449-2464.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Essential role of autophagy in restricting poliovirus infection revealed by identification of an ATG7 defect in a poliomyelitis patient

AU - Brinck Andersen, Nanna Sophie

AU - Jørgensen, Sofie Eg

AU - Skipper, Kristian Alsbjerg

AU - Larsen, Simon Müller

AU - Heinz, Johanna

AU - Thomsen, Michelle Mølgaard

AU - Farahani, Ensieh

AU - Cai, Yujia

AU - Hait, Alon Schneider

AU - Kay, Lise

AU - Giehm Mikkelsen, Jacob

AU - Høgsbjerg Schleimann, Mariane

AU - Thomsen, Martin Kristian

AU - Paludan, Søren R.

AU - Mogensen, Trine H.

PY - 2021/9

Y1 - 2021/9

N2 - 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.

AB - 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.

KW - ATG7

KW - autophagy

KW - host genetics

KW - innate immunity

KW - neuronal-like cells

KW - poliomyelitis

KW - poliovirus

KW - whole exome sequencing

KW - IMMUNITY

KW - DENDRITIC CELLS

KW - RECEPTOR

KW - MACROAUTOPHAGY

KW - INDUCTION

KW - LESSONS

KW - PROTECTS

KW - PATHOGENESIS

KW - PATHOGENICITY

KW - MUTATION

UR - http://www.scopus.com/inward/record.url?scp=85092776550&partnerID=8YFLogxK

U2 - 10.1080/15548627.2020.1831800

DO - 10.1080/15548627.2020.1831800

M3 - Journal article

C2 - 33016799

AN - SCOPUS:85092776550

SN - 1554-8627

VL - 17

SP - 2449

EP - 2464

JO - Autophagy

JF - Autophagy

IS - 9

ER -

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

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