Questions concerning the proximal origin of SARS‐CoV‐2

Seyran, Murat; Pizzol, Damiano; Adadi, Parise; El-Aziz, Tarek Mohamed Abd; Hassan, Sk. Sarif; Soares, António; Kandimalla, Ramesh; Lundström, Kenneth; Tambuwala, Murtaza M.; Aljabali, Alaa A. A.; Lal, Amos; Azad, Gajendra Kumar; Choudhury, Pabitra Pal; Uversky, Vladimir N.; Sherchan, Samendra P.; Uhal, Bruce D.; Rezaei, Nima; Brufsky, Adam

doi:10.1002/jmv.26478

Cited by 67 publications

(54 citation statements)

References 9 publications

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“…Overall, the CD200 was identified by both sequencing the complete genomes (NGS) and the partial RT-PCR (Sanger sequencing) fragment in eight out of 12 EriCoVs tested. This finding is consistent with a template-switching mechanism deemed to underlie the high rate of RNA recombination in CoVs and consequently to represent a possible mechanism at the origin of recombinant CoVs including other CoV or even host related sequences [ 27 , 28 ].…”

Section: Discussionsupporting

confidence: 81%

Can Coronaviruses Steal Genes from the Host as Evidenced in Western European Hedgehogs by EriCoV Genetic Characterization?

Sabato

Bartolo

Marco

et al. 2020

Viruses

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Due to their need for living cells, viruses have developed adaptive evolutionary strategies to survive and perpetuate in reservoir hosts that play a crucial role in the ecology of emerging pathogens. Pathogenic and potentially pandemic betacoronaviruses arose in humans in 2002 (SARS-CoV, disappeared in July 2003), 2012 (MERS-CoV, still circulating in Middle East areas), and 2019 (SARS-CoV-2, causing the current global pandemic). As universally recognized, bats host ancestors of the above-mentioned zoonotic viruses. However, hedgehogs have been recently identified in Europe and Asia as possible reservoirs of MERS-CoV-like strains classified as Erinaceus coronavirus (EriCoV). To elucidate the evolution and genetics of EriCoVs, NGS (next generation sequencing) and Sanger sequencing were used to examine fecal samples collected in Northern Italy in 2018/2019 from 12 hedgehogs previously found EriCoV-positive by RT-PCR. By sequence analysis, eight complete EriCoV genomes, obtained by NGS, showed a high phylogenetic correlation with EriCoV strains previously reported in Eurasia. Interestingly, eight viral strains presented an additional ORF encoding for the CD200 ortholog located between the genes encoding for the Spike and the ORF3a proteins. The CD200 ortholog sequences were closely similar to the host CD200 protein but varying among EriCoVs. The result, confirmed by Sanger sequencing, demonstrates for the first time that CoVs can acquire host genes potentially involved in the immune-modulatory cascade and possibly enabling the virus to escape the host defence.

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Section: Discussionsupporting

confidence: 81%

Can Coronaviruses Steal Genes from the Host as Evidenced in Western European Hedgehogs by EriCoV Genetic Characterization?

Sabato

Bartolo

Marco

et al. 2020

Viruses

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“…This indicates that the bat virus is capable of counteracting the human immune defenses, which may have facilitated successful zoonotic transmission from bat eventually to humans. Currently, the intermediate animal host of SARS-CoV-2 is under debate 3,68–70 , however it is likely, that the virus isolated from it is even closer related to SARS-CoV-2 than RATG13. Thus, any immune evasion mechanisms conserved between SARS-CoV-2 and RATG13, is likely to be conserved in the direct progenitor virus of SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

Imperfect innate immune antagonism renders SARS-CoV-2 vulnerable towards IFN-γ and -λ

Hayn

Hirschenberger

Koepke

et al. 2020

Preprint

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The innate immune system efficiently defends the human host against viral pathogens. Thus, viruses evolved strategies to counteract immune activation. Here, we systematically analysed the impact of 29 SARS-CoV-2 encoded proteins on three major arms of our cell-intrinsic innate immune defences: interferon (IFN) induction, cytokine signalling and autophagy. Subsequent mechanistic analyses revealed that SARS-CoV-2 proteins target the respective signalling cascades at multiple steps. For example, we show that Nsp14 reduces endogenous IFN receptor levels and ORF3a and ORF7a perturb the late endosomal/trans-Golgi network. Our data demonstrates that most antagonistic activities are conserved between proteins encoded by SARS-CoV-2, the closely related bat RaTG13-CoV and the highly pathogenic SARS-CoV-1. However, SARS-CoV-1 Nsp15 is strikingly more potent in suppressing IFN induction and signalling than its SARS-CoV-2 counterpart. This may help explain the lower pathogenicity of SARS-CoV-2, which facilitated its rapid spread. Overall our analyses revealed that IFN-γ and IFN-λ1 signalling are antagonised the least, leaving SARS-CoV-2 highly susceptible to these two cytokines. Their combination synergistically potentiated the anti-viral effects against SARS-CoV-2 at low concentrations. Taken together, our results allow an explanation for differences in susceptibility towards IFNs and provide evidence that rational immune activation may be an effective future therapeutic strategy against SARS-CoV-2.

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“…Therefore, it is possible to exclude that such insertion could have originated by polymerase slippage or by releasing and repriming, because insertion mutations generated by these mechanisms have been postulated to maintain the reading frame of the viral sequence. [ 46 ] The possibility that the furin cleavage site could have been acquired by recombination has been recently questioned by Seyran et al., [ 47 ] because the SARS‐CoV‐2 spike protein seems to lack any further recombination event in contrast with the recombination model of other CoVs.…”

Section: The Furin Cleavage Site: the Key Difference Between Sars‐covmentioning

confidence: 99%

The genetic structure of SARS‐CoV‐2 does not rule out a laboratory origin

Segreto

Deigin²

2020

BioEssays

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Severe acute respiratory syndrome‐coronavirus (SARS‐CoV)‐2′s origin is still controversial. Genomic analyses show SARS‐CoV‐2 likely to be chimeric, most of its sequence closest to bat CoV RaTG13, whereas its receptor binding domain (RBD) is almost identical to that of a pangolin CoV. Chimeric viruses can arise via natural recombination or human intervention. The furin cleavage site in the spike protein of SARS‐CoV‐2 confers to the virus the ability to cross species and tissue barriers, but was previously unseen in other SARS‐like CoVs. Might genetic manipulations have been performed in order to evaluate pangolins as possible intermediate hosts for bat‐derived CoVs that were originally unable to bind to human receptors? Both cleavage site and specific RBD could result from site‐directed mutagenesis, a procedure that does not leave a trace. Considering the devastating impact of SARS‐CoV‐2 and importance of preventing future pandemics, researchers have a responsibility to carry out a thorough analysis of all possible SARS‐CoV‐2 origins.

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Questions concerning the proximal origin of SARS‐CoV‐2

Cited by 67 publications

References 9 publications

Can Coronaviruses Steal Genes from the Host as Evidenced in Western European Hedgehogs by EriCoV Genetic Characterization?

Can Coronaviruses Steal Genes from the Host as Evidenced in Western European Hedgehogs by EriCoV Genetic Characterization?

Imperfect innate immune antagonism renders SARS-CoV-2 vulnerable towards IFN-γ and -λ

The genetic structure of SARS‐CoV‐2 does not rule out a laboratory origin

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