SARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans

ABSTRACT Recent evidence shows that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sensitive to interferons (IFNs). However, the most effective types of IFNs and the underlying antiviral effectors remain to be defined. Here, we show that zinc finger antiviral protein (ZAP), which pr...

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Autores principales:	Rayhane Nchioua, Dorota Kmiec, Janis A. Müller, Carina Conzelmann, Rüdiger Groß, Chad M. Swanson, Stuart J. D. Neil, Steffen Stenger, Daniel Sauter, Jan Münch, Konstantin M. J. Sparrer, Frank Kirchhoff
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	COVID-19 CpG suppression SARS-CoV-2 ZAP evolution interferon Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ce8641cdf3aa423a894bfbb5ce1d791c
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spelling	oai:doaj.org-article:ce8641cdf3aa423a894bfbb5ce1d791c2021-11-15T16:19:09ZSARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans10.1128/mBio.01930-202150-7511https://doaj.org/article/ce8641cdf3aa423a894bfbb5ce1d791c2020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01930-20https://doaj.org/toc/2150-7511ABSTRACT Recent evidence shows that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sensitive to interferons (IFNs). However, the most effective types of IFNs and the underlying antiviral effectors remain to be defined. Here, we show that zinc finger antiviral protein (ZAP), which preferentially targets CpG dinucleotides in viral RNA sequences, restricts SARS-CoV-2. We further demonstrate that ZAP and its cofactors KHNYN and TRIM25 are expressed in human lung cells. Type I, II, and III IFNs all strongly inhibited SARS-CoV-2 and further induced ZAP expression. Comprehensive sequence analyses revealed that SARS-CoV-2 and its closest relatives from horseshoe bats showed the strongest CpG suppression among all known human and bat coronaviruses, respectively. Nevertheless, endogenous ZAP expression restricted SARS-CoV-2 replication in human lung cells, particularly upon treatment with IFN-α or IFN-γ. Both the long and the short isoforms of human ZAP reduced SARS-CoV-2 RNA expression levels, but the former did so with greater efficiency. Finally, we show that the ability to restrict SARS-CoV-2 is conserved in ZAP orthologues of the reservoir bat and potential intermediate pangolin hosts of human coronaviruses. Altogether, our results show that ZAP is an important effector of the innate response against SARS-CoV-2, although this pandemic pathogen emerged from zoonosis of a coronavirus that was preadapted to the low-CpG environment in humans. IMPORTANCE Although interferons inhibit SARS-CoV-2 and have been evaluated for treatment of coronavirus disease 2019 (COVID-19), the most effective types and antiviral effectors remain to be defined. Here, we show that IFN-γ is particularly potent in restricting SARS-CoV-2 and in inducing expression of the antiviral factor ZAP in human lung cells. Knockdown experiments revealed that endogenous ZAP significantly restricts SARS-CoV-2. We further show that CpG dinucleotides which are specifically targeted by ZAP are strongly suppressed in the SARS-CoV-2 genome and that the two closest horseshoe bat relatives of SARS-CoV-2 show the lowest genomic CpG content of all coronavirus sequences available from this reservoir host. Nonetheless, both the short and long isoforms of human ZAP reduced SARS-CoV-2 RNA levels, and this activity was conserved in horseshoe bat and pangolin ZAP orthologues. Our findings indicating that type II interferon is particularly efficient against SARS-CoV-2 and that ZAP restricts this pandemic viral pathogen might promote the development of effective immune therapies against COVID-19.Rayhane NchiouaDorota KmiecJanis A. MüllerCarina ConzelmannRüdiger GroßChad M. SwansonStuart J. D. NeilSteffen StengerDaniel SauterJan MünchKonstantin M. J. SparrerFrank KirchhoffAmerican Society for MicrobiologyarticleCOVID-19CpG suppressionSARS-CoV-2ZAPevolutioninterferonMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 CpG suppression SARS-CoV-2 ZAP evolution interferon Microbiology QR1-502
spellingShingle	COVID-19 CpG suppression SARS-CoV-2 ZAP evolution interferon Microbiology QR1-502 Rayhane Nchioua Dorota Kmiec Janis A. Müller Carina Conzelmann Rüdiger Groß Chad M. Swanson Stuart J. D. Neil Steffen Stenger Daniel Sauter Jan Münch Konstantin M. J. Sparrer Frank Kirchhoff SARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans
description	ABSTRACT Recent evidence shows that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sensitive to interferons (IFNs). However, the most effective types of IFNs and the underlying antiviral effectors remain to be defined. Here, we show that zinc finger antiviral protein (ZAP), which preferentially targets CpG dinucleotides in viral RNA sequences, restricts SARS-CoV-2. We further demonstrate that ZAP and its cofactors KHNYN and TRIM25 are expressed in human lung cells. Type I, II, and III IFNs all strongly inhibited SARS-CoV-2 and further induced ZAP expression. Comprehensive sequence analyses revealed that SARS-CoV-2 and its closest relatives from horseshoe bats showed the strongest CpG suppression among all known human and bat coronaviruses, respectively. Nevertheless, endogenous ZAP expression restricted SARS-CoV-2 replication in human lung cells, particularly upon treatment with IFN-α or IFN-γ. Both the long and the short isoforms of human ZAP reduced SARS-CoV-2 RNA expression levels, but the former did so with greater efficiency. Finally, we show that the ability to restrict SARS-CoV-2 is conserved in ZAP orthologues of the reservoir bat and potential intermediate pangolin hosts of human coronaviruses. Altogether, our results show that ZAP is an important effector of the innate response against SARS-CoV-2, although this pandemic pathogen emerged from zoonosis of a coronavirus that was preadapted to the low-CpG environment in humans. IMPORTANCE Although interferons inhibit SARS-CoV-2 and have been evaluated for treatment of coronavirus disease 2019 (COVID-19), the most effective types and antiviral effectors remain to be defined. Here, we show that IFN-γ is particularly potent in restricting SARS-CoV-2 and in inducing expression of the antiviral factor ZAP in human lung cells. Knockdown experiments revealed that endogenous ZAP significantly restricts SARS-CoV-2. We further show that CpG dinucleotides which are specifically targeted by ZAP are strongly suppressed in the SARS-CoV-2 genome and that the two closest horseshoe bat relatives of SARS-CoV-2 show the lowest genomic CpG content of all coronavirus sequences available from this reservoir host. Nonetheless, both the short and long isoforms of human ZAP reduced SARS-CoV-2 RNA levels, and this activity was conserved in horseshoe bat and pangolin ZAP orthologues. Our findings indicating that type II interferon is particularly efficient against SARS-CoV-2 and that ZAP restricts this pandemic viral pathogen might promote the development of effective immune therapies against COVID-19.
format	article
author	Rayhane Nchioua Dorota Kmiec Janis A. Müller Carina Conzelmann Rüdiger Groß Chad M. Swanson Stuart J. D. Neil Steffen Stenger Daniel Sauter Jan Münch Konstantin M. J. Sparrer Frank Kirchhoff
author_facet	Rayhane Nchioua Dorota Kmiec Janis A. Müller Carina Conzelmann Rüdiger Groß Chad M. Swanson Stuart J. D. Neil Steffen Stenger Daniel Sauter Jan Münch Konstantin M. J. Sparrer Frank Kirchhoff
author_sort	Rayhane Nchioua
title	SARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans
title_short	SARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans
title_full	SARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans
title_fullStr	SARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans
title_full_unstemmed	SARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans
title_sort	sars-cov-2 is restricted by zinc finger antiviral protein despite preadaptation to the low-cpg environment in humans
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/ce8641cdf3aa423a894bfbb5ce1d791c
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SARS-CoV-2 Is Restricted by Zinc Finger Antiviral Protein despite Preadaptation to the Low-CpG Environment in Humans

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