Unheeded SARS-CoV-2 proteins? A deep look into negative-sense RNA

Bartas, Martin; Volná, Adriana; Brázda, Václav; Červeň, Jiří; Pečínka, Petr

doi:10.1101/2020.11.27.400788

Cited by 5 publications

(4 citation statements)

References 110 publications

(143 reference statements)

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“…TISRover appeared to favour the mutant start-gain uORF (score: 9.2×10 -5 ) over the wild-type uORF (score: 1×10 -6 ) as a translation initiation site (TIS), although both scored lower than the canonical start codon (score: 2.8×10 -2 ) (Figure 4C and Supplementary Table 1F). One study used a TISRover score cut-off of 0.1 to annotate translation initiation sites (45). Another TIS prediction algorithm, TIS Transformer, did not annotate either the wild-type or mutant uORFs as potential TIS (38).…”

Section: Immunopeptidomic Discoverymentioning

confidence: 99%

Untranslated regions (UTRs) are a potential novel source of neoantigens for personalised immunotherapy

Sng,

Kallor,

Simpson

et al. 2024

Front. Immunol.

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BackgroundNeoantigens, mutated tumour-specific antigens, are key targets of anti-tumour immunity during checkpoint inhibitor (CPI) treatment. Their identification is fundamental to designing neoantigen-directed therapy. Non-canonical neoantigens arising from the untranslated regions (UTR) of the genome are an overlooked source of immunogenic neoantigens. Here, we describe the landscape of UTR-derived neoantigens and release a computational tool, PrimeCUTR, to predict UTR neoantigens generated by start-gain and stop-loss mutations.MethodsWe applied PrimeCUTR to a whole genome sequencing dataset of pre-treatment tumour samples from CPI-treated patients (n = 341). Cancer immunopeptidomic datasets were interrogated to identify MHC class I presentation of UTR neoantigens.ResultsStart-gain neoantigens were predicted in 72.7% of patients, while stop-loss mutations were found in 19.3% of patients. While UTR neoantigens only accounted 2.6% of total predicted neoantigen burden, they contributed 12.4% of neoantigens with high dissimilarity to self-proteome. More start-gain neoantigens were found in CPI responders, but this relationship was not significant when correcting for tumour mutational burden. While most UTR neoantigens are private, we identified two recurrent start-gain mutations in melanoma. Using immunopeptidomic datasets, we identify two distinct MHC class I-presented UTR neoantigens: one from a recurrent start-gain mutation in melanoma, and one private to Jurkat cells.ConclusionPrimeCUTR is a novel tool which complements existing neoantigen discovery approaches and has potential to increase the detection yield of neoantigens in personalised therapeutics, particularly for neoantigens with high dissimilarity to self. Further studies are warranted to confirm the expression and immunogenicity of UTR neoantigens.

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Section: Immunopeptidomic Discoverymentioning

confidence: 99%

Untranslated regions (UTRs) are a potential novel source of neoantigens for personalised immunotherapy

Sng,

Kallor,

Simpson

et al. 2024

Front. Immunol.

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“…The RNA is then replicated to form new virions released to infect neighboring host cells 43 . The genome of SARS-CoV-2 is one of the largest among known RNA viruses, comprising of at least 26 identified protein-coding loci 44 . Positive-sense RNA viruses like SARS-CoV-2 were previously thought to encode proteins solely on the positive strand.…”

Section: Covid-19 Pathophysiologymentioning

confidence: 99%

The Emerging Role of Photobiomodulation in COVID-19 Therapy – Part I

Williams

2023

MRAJ

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Background. Infectivity, genomic variability, and symptomatic diversity of the SARS-CoV-2 virus represents a persistent challenge in the treatment of acute and long COVID-19 diseases. A direct consequence of pervasive ACE-2 receptors susceptible to the virion’s spike protein, disease trajectories commence as upper respiratory infection migrating into bronchia (presenting coughing, dyspnea, and fever), followed by viremic infection and circulatory distress from inflammation of visceral epithelium and vascular endothelia, decreased blood perfusion, and hypoxia. Severe cases include hyperinflammation, cytokine storms, and multisystem inflammatory syndrome with lung and nerve damage, and chronic cognitive deficits. Method. This paper (Part I) considers the requirements for treating acute and chronic COVID-19 with deep-tissue photobiomodulation (PBM) of sinuses, lungs and other ACE-2 populated organs using transdermal and transcranial light as a primary therapeutic modality. Analysis. A detailed analysis of optics, biophysics, numerical simulations, and quantum photochemistry for non-invasive deep tissue PBM of SARS-CoV-2 infected organs was performed including optical design, photonic control, irradiance, fluence, modulation, and protocols. Results. Analysis concludes large-area 3D bendable LED pads are best suited for deep-tissue PBM to transdermally treat whole-organ infection of the lungs, sinuses, abdominal cavity (and to transcranially treat long-COVID). Robotic laser scanning represents another viable option for deep-tissue PBM provided the optical angle of incidence is minimal. Penetration depth depends on wavelength (not optical power) with red (635nm) and NIR (850nm) shown to adequately penetrate through cutaneious tissue and parietal fascia into viscera. Conclusions. Red and NIR LEDs with average pulsed irradiances of 8.5 and 13.5 mW/cm2 respectively deliver hands-free whole-organ deep-tissue doses of between 0.5 to 4.0 J/cm2 in 60 min sessions from a surface dose of Pl/A = 40 J/cm2 depending on tissue transmission coefficients Yx at depth x>6mm. The designed photonic PBM system performs algorithmic variable frequency pulsed protocols covering up to 1,200 cm2. Duty factor control limits skin temperatures below 43°C irrespective of pulse modulating frequency. A mechanistic model for deep-tissue PBM, phenomenologically consistent with biophysics, photon penetration studies, COVID disease trajectories, and patient recovery profiles is presented. Part II details various acute and chronic case studies and positive outcomes thereof confirming PBM as a efficacious modality for COVID-19.

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“…Since little has been reported on the functionality of ORF2b or ORF-Sh in infected cells (although translation of ORF-Sh is still to be confirmed) and no homologous domains were found using sequence analysis tools, we used structural bioinformatics methodologies, as previously performed to elucidate the threedimensional features of the SARS-CoV-2 proteome, to model the structural characteristics both ORFs (52)(53)(54)(55)(56)(57)(58)(59)(60)(61). As shown in Figure 1A, the majority of the ORF2b protein is predicted to be fixed in the membrane (62).…”

Section: Overlapping Orfs On the Sars-cov-2 Spike Protein Nucleotide ...mentioning

confidence: 99%

Are There Hidden Genes in DNA/RNA Vaccines?

et al. 2022

Self Cite

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Due to the fast global spreading of the Severe Acute Respiratory Syndrome Coronavirus – 2 (SARS-CoV-2), prevention and treatment options are direly needed in order to control infection-related morbidity, mortality, and economic losses. Although drug and inactivated and attenuated virus vaccine development can require significant amounts of time and resources, DNA and RNA vaccines offer a quick, simple, and cheap treatment alternative, even when produced on a large scale. The spike protein, which has been shown as the most antigenic SARS-CoV-2 protein, has been widely selected as the target of choice for DNA/RNA vaccines. Vaccination campaigns have reported high vaccination rates and protection, but numerous unintended effects, ranging from muscle pain to death, have led to concerns about the safety of RNA/DNA vaccines. In parallel to these studies, several open reading frames (ORFs) have been found to be overlapping SARS-CoV-2 accessory genes, two of which, ORF2b and ORF-Sh, overlap the spike protein sequence. Thus, the presence of these, and potentially other ORFs on SARS-CoV-2 DNA/RNA vaccines, could lead to the translation of undesired proteins during vaccination. Herein, we discuss the translation of overlapping genes in connection with DNA/RNA vaccines. Two mRNA vaccine spike protein sequences, which have been made publicly-available, were compared to the wild-type sequence in order to uncover possible differences in putative overlapping ORFs. Notably, the Moderna mRNA-1273 vaccine sequence is predicted to contain no frameshifted ORFs on the positive sense strand, which highlights the utility of codon optimization in DNA/RNA vaccine design to remove undesired overlapping ORFs. Since little information is available on ORF2b or ORF-Sh, we use structural bioinformatics techniques to investigate the structure-function relationship of these proteins. The presence of putative ORFs on DNA/RNA vaccine candidates implies that overlapping genes may contribute to the translation of smaller peptides, potentially leading to unintended clinical outcomes, and that the protein-coding potential of DNA/RNA vaccines should be rigorously examined prior to administration.

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Unheeded SARS-CoV-2 proteins? A deep look into negative-sense RNA

Cited by 5 publications

References 110 publications

Untranslated regions (UTRs) are a potential novel source of neoantigens for personalised immunotherapy

Untranslated regions (UTRs) are a potential novel source of neoantigens for personalised immunotherapy

The Emerging Role of Photobiomodulation in COVID-19 Therapy – Part I

Are There Hidden Genes in DNA/RNA Vaccines?

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