The Zinc Finger Antiviral Protein restricts SARS-CoV-2

Nchioua, Rayhane; Mueller, Janis A; Conzelmann, Carina; Gross, Ruediger; Stenger, Steffen; Sauter, Daniel; Muench, Jan; Sparrer, Konstantin M. J.; Kirchhoff, Frank

doi:10.1101/2020.06.04.134379

Cited by 14 publications

(27 citation statements)

References 56 publications

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“…After our work was posted on the bioarxiv, R. Nchioua and colleagues have shown the importance of ZAP in controlling the response against SARS-CoV-2, see [37], by demonstrating that a knock-out of this protein increases SARS-CoV-2 replication. This finding supports our prediction that recognition of SARS-CoV-2 by ZAP imposes a significant fitness cost on the virus, as demonstrated by its early evolution to remove ZAP recognition motifs.…”

Section: Discussionmentioning

confidence: 99%

The heterogeneous landscape and early evolution of pathogen-associated CpG dinucleotides in SARS-CoV-2

Gioacchino

Šulc

Komarova

et al. 2020

Preprint

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SARS-CoV-2 infection can lead to acute respiratory syndrome in patients, which can be due in part to dysregulated immune signalling. We analyze here the occurrences of CpG and UpA dinucleotides, which are putative pathogen-associated molecular patterns, along the viral sequence. Carrying out a comparative analysis with other ssRNA viruses and within the Coronaviridae family, we find the CpG content of SARS-CoV-2, while low compared to other betacoronaviruses, widely fluctuates along its primary sequence. While the CpG relative abundance and its associated CpG force parameter [1] are low for the spike protein (S) and comparable to circulating seasonal coronaviruses such as HKU1, they are much greater and comparable to SARS and MERS for the 3'-end of the viral genome. In particular, the nucleocapsid protein (N), whose transcripts are relatively abundant in the cytoplasm of infected cells and present in the 3'UTRs of all subgenomic RNA, has high CpG content. We speculate this dual nature of CpG content can confer to SARS-CoV-2 high ability to both enter the host and trigger pattern recognition receptors (PRRs) in different contexts. We then investigate the evolution of synonymous mutations since the outbreak of the COVID-19 pandemic. Using a new application of selective forces on dinucleotides to estimate context driven mutational processes, we find that synonymous mutations seem driven both by the viral codon bias and by the high value of the CpG force in the N protein, leading to a loss in CpG content. Sequence motifs preceding these CpG-loss-associated loci match recently identified binding patterns of the Zinc Finger anti-viral Protein (ZAP) protein.

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Section: Discussionmentioning

confidence: 99%

The heterogeneous landscape and early evolution of pathogen-associated CpG dinucleotides in SARS-CoV-2

Gioacchino

Šulc

Komarova

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…ISGs positively potentiating IFN signaling, such as IFIH1/MDA5, TANK, IRF7, and STAT1, were also increased in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients as compared with healthy controls [105] and could potentially contribute to the amplification of IFN-I response against SARS-CoV-2 replication. Zinc finger antiviral protein (ZAP), which is encoded by an ISG, contributes to the anti-SARS-CoV-2 effect of IFNs in human lung Calu-3 cells [114]. ZAP is known for restricting the replication of numerous viruses such as retroviruses and filoviruses [115].…”

Section: Detrimental Effects Of Ifns On Sars-cov-2 Replicationmentioning

confidence: 99%

Interplay between SARS-CoV-2 and the type I interferon response

et al. 2020

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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. An unbalanced immune response, characterized by a weak production of type I interferons (IFN-Is) and an exacerbated release of proinflammatory cytokines, contributes to the severe forms of the disease. SARS-CoV-2 is genetically related to SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV), which caused outbreaks in 2003 and 2013, respectively. Although IFN treatment gave some encouraging results against SARS-CoV and MERS-CoV in animal models, its potential as a therapeutic against COVID-19 awaits validation. Here, we describe our current knowledge of the complex interplay between SARS-CoV-2 infection and the IFN system, highlighting some of the gaps that need to be filled for a better understanding of the underlying molecular mechanisms. In addition to the conserved IFN evasion strategies that are likely shared with SARS-CoV and MERS-CoV, novel counteraction mechanisms are being discovered in SARS-CoV-2-infected cells. Since the last coronavirus epidemic, we have made considerable progress in understanding the IFN-I response, including its spatiotemporal regulation and the prominent role of plasmacytoid dendritic cells (pDCs), which are the main IFN-I-producing cells. While awaiting the results of the many clinical trials that are evaluating the efficacy of IFN-I alone or in combination with antiviral molecules, we discuss the potential benefits of a well-timed IFN-I treatment and propose strategies to boost pDC-mediated IFN responses during the early stages of viral infection.

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“…Various host antiviral mechanisms accelerate the depletion of CpG dinucleotides (a cytosine followed by a guanine in the 5' to 3' direction) in virus genomes. This is thought to be primarily mediated either through selective pressures by a CpG-targeting mechanism involving the Zinc finger Antiviral Protein (ZAP) 42 or C to U hypermutation by APOBEC3 cytidine deaminases 43 , and recent work has demonstrated that the CpG binding ZAP protein inhibits SARS-CoV-2 replication in human lung cells 44 . These forces are likely to vary across tissues and between hosts.…”

Section: Patterns Of Cpg Depletion In the Ncov Clade Genome Compositmentioning

confidence: 99%

Natural selection in the evolution of SARS-CoV-2 in bats, not humans, created a highly capable human pathogen

MacLean

Lytras

Weaver

et al. 2020

Preprint

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RNA viruses are proficient at switching to novel host species due to their fast mutation rates. Implicit in this assumption is the need to evolve adaptations in the new host species to exploit their cells efficiently. However, SARS-CoV-2 has required no significant adaptation to humans since the pandemic began, with no observed selective sweeps to date. Here we contrast the role of positive selection and recombination in the Sarbecoviruses in horseshoe bats to SARS-CoV-2 evolution in humans. While methods can detect some evidence for positive selection in SARS-CoV-2, we demonstrate these are mostly due to recombination and sequencing artefacts.Purifying selection is also substantially weaker in SARS-CoV-2 than in the related bat Sarbecoviruses. In comparison, our results show evidence for positive, specifically episodic selection, acting on the bat virus lineage SARS-CoV-2 emerged from. This signature of selection can also be observed among synonymous substitutions, for example, linked to ancestral CpG depletion on this bat lineage. We show the bat virus RmYN02 has recombinant CpG content in Spike pointing to coinfection and evolution in bats without involvement of other species. Our results suggest the non-human progenitor of SARS-CoV-2 was capable of humanhuman transmission as a consequence of its natural evolution in bats. Main textIn December 2019, a novel coronavirus emerged in the city of Wuhan, China, causing coronavirus disease-2019 (COVID-19) characterised by respiratory or gastrointestinal viral symptoms, and in severe cases, additionally, acute respiratory distress syndrome, cardiovascular dysfunction, thrombosis and other symptoms 1 . Evolutionary analysis placed this new human virus in the same subgenus of Betacoronavirus, the Sarbecoviruses (Figure 1A), that SARS emerged from 2 , and it was named SARS-CoV-2 3 -the seventh known humaninfecting member of the Coronaviridae. The initial outbreak of human cases of the virus was connected to the Huanan Seafood Wholesale Market in Wuhan 4 , and while related viruses have been found in horseshoe bats 5 and pangolins 6 , their divergence represents decades of evolution 7 leaving the direct origin of the pandemic unknown. In addition to the importance of understanding the route from animals to humans, key questions for assessing future risk of emergence are: what is the extent of evolution required to permit a bat virus to transmit to humans, and what subsequent evolution needs to occur for efficient transmission once the virus is established within the human population?While both the first SARS virus outbreak in 2002/2003, causing approximately 8,000 infections, and a re-emergence in late 2003, causing four infections, were linked to Himalayan palm civets and raccoon dogs in marketplaces in Guangdong province 8,9 , it became clear that these animals were conduits for spillover to humans and not true viral reservoirs 10 . Extensive surveillance work subsequently identified related viruses circulating in horseshoe bats in China some of which can replicate rea...

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The Zinc Finger Antiviral Protein restricts SARS-CoV-2

Cited by 14 publications

References 56 publications

The heterogeneous landscape and early evolution of pathogen-associated CpG dinucleotides in SARS-CoV-2

The heterogeneous landscape and early evolution of pathogen-associated CpG dinucleotides in SARS-CoV-2

Interplay between SARS-CoV-2 and the type I interferon response

Natural selection in the evolution of SARS-CoV-2 in bats, not humans, created a highly capable human pathogen

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