Nuclear translocation of spike mRNA and protein is a novel pathogenic feature of SARS-CoV-2

Sattar, Sarah; Kabát, Juraj; Jerome, Kailey; Feldmann, Friederike; Bailey, Kristina L.; Mehedi, Masfique

doi:10.1101/2022.09.27.509633

Cited by 8 publications

(13 citation statements)

References 56 publications

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“…In this study, S1 was highly aggregated around and in the nucleus under confocal microscopy (unpublished data). Therefore, we assumed that the potential mechanisms of S1 in the nucleus might be via NPCs, which was recently clarified by Sattar et al 37 .…”

Section: Discussionmentioning

confidence: 98%

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Analysis of the SARS-CoV-2 spike protein revealed that blocked receptor-binding domain antigenicity decreases the production of neutralizing antibodies in vivo

Mei

Zhang

Hammond

et al. 2023

Preprint

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The identification of SARS-CoV-2 spike protein distribution and function in target cells has raised concerns about its possible impacts on vaccine efficacy and pathogenic effect in host cells. Thus, a better understanding of such consequences is necessary. In this study, we studied the biological characteristics of six variants of SARS-CoV-2 in A549 and HEK293 cells using four different technologies. The results showed that compared to the other fragments, the full-length spike protein exhibited the highest expression on the cell surface and was detectable in the cell supernatant, cytoplasm, and nucleus. Except for the cell surface, the S1 subunit generally expressed higher than the full-length spike protein. RBD and S2 subunits were expressed in the cytoskeleton. The SS-RBD peptide, which consists of a 19-amino acid signal peptide sequence (SS)-linked RBD, exhibited the highest expression in the cell supernatant among all other studied peptides. The SS positively enhanced the expression, migration, and secretion of SS-RBD from the cytoskeleton to the supernatant. Importantly, the FACS assay results showed that neutralizing antibodies (NAbs) could recognize SS-RBD but not RBD in the transfected cells, suggesting that RBD was tightly bound by ACE2 in HEK293 cells. In contrast, the antigenicity of the RBD in the spike protein was revealed and efficiently monitored only by 6-His-tag mAbs. Thus, our findings demonstrated that ACE2 blocks crucial immunogenic epitopes of the RBD, and the full-length spike protein mainly induces non-neutralizing antibodies in vivo. Therefore, we suggest that reducing ACE2 binding affinity and exposing the immunogenicity of the RBD on the spike protein is imperative for improving vaccine efficacy and generating new SARS-CoV-2 mRNA vaccines.

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Section: Discussionmentioning

confidence: 98%

“…Therefore, we assumed that the potential mechanisms of S1 in the nucleus might be via NPCs, which was recently clarified by Sattar et al . 37 .…”

Section: Discussionmentioning

confidence: 99%

Analysis of the SARS-CoV-2 spike protein revealed that blocked receptor-binding domain antigenicity decreases the production of neutralizing antibodies in vivo

Mei

Zhang

Hammond

et al. 2023

Preprint

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“…• Notably, for CoVs, mRNA transcription is done in a discontinuous manner (Lai, 1996;Rowe et al, 1997), with the viral polymerase functioning in a piecemeal fashion rather than progressing the entire viral genome at once. This fact is well established, as summarized by a recent publication by the NIAID (Sattar et al, 2023): "These coronaviruses contain a positive-strand RNA genome with a few unique features: twothirds of the viral RNA is translated into a large polyprotein, and the remainder of the viral genome is transcribed by a discontinuous transcription process into a nested set of subgenomic mRNAs." • Necessary for the above discontinuous mechanism is that the viral polymerase and nascent RNA transcripts disassociate from the RNA template regularly during RNA transcription, and by necessity then, the CoV polymerase must jump between different RNA molecules during RNA synthesis (Lai, 1996).…”

Section: Feasibility Of Integration Of a Short Stretch Of Synthetic R...mentioning

confidence: 99%

Recombination between coronaviruses and synthetic RNAs and biorisk implications motivated by a SARS-CoV-2 FCS origin controversy

Mueller¹

2023

Front. Bioeng. Biotechnol.

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The urgent need for improved policy, regulation, and oversight of research with potential pandemic pathogens (PPPs) has been widely acknowledged. A 2022 article in Frontiers in Virology raises questions, reporting on a 100% sequence homology between the SARS-CoV-2 furin cleavage site (FCS) and the negative strand of a 2017 patented sequence. Even though Ambati and collaborators suspect a possible inadvertent or intentional cause leading to the FCS insert, the related underpinnings have not been studied from the perspective of potential biorisk policy gaps. A commentary on their article contests the low coincidence likelihood that was calculated by Ambati et al., arguing that the sequence match could have been a chance occurrence alone. Additionally, it has been suggested that the odds of the recombination event may be low. These considerations seem to have put many speculations related to any implied viral beginnings, notably from a research setting likely outside the Wuhan Institute of Virology, to rest. However, potential implications for future disasters in terms of biosafety and biosecurity have not been addressed. To demonstrate the feasibility of the Ambati et al. postulate, a theoretical framework is developed that substantially extends the research orientations implicated by these authors and the related patent. It is argued that specific experimental conditions, in combination, could significantly increase the implied recombination profile between coronaviruses and synthetic RNAs. Consequently, this article scrutinizes these largely unrecognized vulnerabilities to discuss implications across the spectrum of the biological risk landscape, with special attention to a potential “crime harvest.” Focusing on insufficiently understood features of interaction between the natural and man-made world, vulnerabilities related to contaminants, camouflaging, and various misuse potentials fostered by the digitization and computerization of synthetic biology, it highlights novel biorisk gaps not covered by existing PPP policy. Even though this work does not aim to provide proof of the viral origin, it will make the point that, in theory, a convergence of under-appreciated lab experiments and technologies could have led to the SARS-CoV-2 FCS insert, which analogously could be exploited by various threat actors for the clandestine genesis of similar or even worse pathogens.

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“…In conclusion, there are a myriad of reports about the pathogenic effects of Spike of SARS-CoV-2 (regarding the Spike of the initial variants) in the current literature. One preprint publication on Spike demonstrated that the protein enters the nucleus in human epithelial cells due to presence of a novel nuclear localization signal [ 163 ], which is absent in other coronaviruses. Spike could shuttle mRNA into the nucleus, a phenomenon that could have several implications for the genetic maintenance of cells [ 164 ].…”

Section: Possible Mechanisms Of Covid-19 Mrna Vaccine-induced Tissue/...mentioning

confidence: 99%

Safety of COVID-19 Vaccines in Patients with Autoimmune Diseases, in Patients with Cardiac Issues, and in the Healthy Population

2023

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The coronavirus disease 2019 (COVID-19) has been a challenge for the whole world since the beginning of 2020, and COVID-19 vaccines were considered crucial for disease eradication. Instead of producing classic vaccines, some companies pointed to develop products that mainly function by inducing, into the host, the production of the antigenic protein of SARS-CoV-2 called Spike, injecting an instruction based on RNA or a DNA sequence. Here, we aim to give an overview of the safety profile and the actual known adverse effects of these products in relationship with their mechanism of action. We discuss the use and safety of these products in at-risk people, especially those with autoimmune diseases or with previously reported myocarditis, but also in the general population. We debate the real necessity of administering these products with unclear long-term effects to at-risk people with autoimmune conditions, as well as to healthy people, at the time of omicron variants. This, considering the existence of therapeutic interventions, much more clearly assessed at present compared to the past, and the relatively lower aggressive nature of the new viral variants.

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Nuclear translocation of spike mRNA and protein is a novel pathogenic feature of SARS-CoV-2

Cited by 8 publications

References 56 publications

Analysis of the SARS-CoV-2 spike protein revealed that blocked receptor-binding domain antigenicity decreases the production of neutralizing antibodies in vivo

Analysis of the SARS-CoV-2 spike protein revealed that blocked receptor-binding domain antigenicity decreases the production of neutralizing antibodies in vivo

Recombination between coronaviruses and synthetic RNAs and biorisk implications motivated by a SARS-CoV-2 FCS origin controversy

Safety of COVID-19 Vaccines in Patients with Autoimmune Diseases, in Patients with Cardiac Issues, and in the Healthy Population

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