Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach

Naqvi, Ahmad Abu Turab; Fatima, Kisa; Mohammad, Taj; Fatima, Urooj; Singh, Ishwar; Singh, Archana; Atif, Shaikh M.; Hariprasad, Gururao; Hasan, Gulam Mustafa; Hassan, Imtaiyaz

doi:10.1016/j.bbadis.2020.165878

Cited by 843 publications

(850 citation statements)

References 150 publications

(152 reference statements)

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“…ORF9c is present in previously characterized strains of SARS-CoV (37), a conservation suggesting a function in coronavirus pathogenesis. Phylogenetic analysis and alignment of the protein sequences showed that mutations are present in ORF9c among different coronavirus strains with bat SARS-like coronavirus ORF14 as the closest ortholog sharing 94% sequence identity and only 77% identity with ORF14 of SARS-CoV (Fig.…”

Section: Sars-cov-2 Orf9c Encodes An Unstable Protein With a Putativementioning

confidence: 98%

SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells

Andres

Feng

Campos

et al. 2020

Preprint

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Disrupted antiviral immune responses are associated with severe COVID-19, the disease caused by SAR-CoV-2. Here, we show that the 73-amino-acid protein encoded by ORF9c of the viral genome contains a putative transmembrane domain, interacts with membrane proteins in multiple cellular compartments, and impairs antiviral processes in a lung epithelial cell line. Proteomic, interactome, and transcriptomic analyses, combined with bioinformatic analysis, revealed that expression of only this highly unstable small viral protein impaired interferon signaling, antigen presentation, and complement signaling, while inducing IL-6 signaling. Furthermore, we showed that interfering with ORF9c degradation by either proteasome inhibition or inhibition of the ATPase VCP blunted the effects of ORF9c. Our study indicated that ORF9c enables immune evasion and coordinates cellular changes essential for the SARS-CoV-2 life cycle.

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Section: Sars-cov-2 Orf9c Encodes An Unstable Protein With a Putativementioning

confidence: 98%

SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells

Andres

Feng

Campos

et al. 2020

Preprint

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“…MHV-A59 has been previously shown to cause pneumonia in C57Bl6/J mice (Coronaviridae Study Group of the International Committee on Taxonomy of, 2020; Yang et al, 2014), unlike other MHV strains that require A/J, C3H/HeJ, or other backgrounds to develop pneumonia (DeAlbuquerque et al, 2006;Leibowitz et al, 2010). As seen in Supplemental Figure 1A, SARS-CoV-2 and MHV-A59 belong to the same phylogenetic clade (adapted from (Gorbalenya et al, 2004)), have highly similar genomic structure (Supplemental Figure 1B) (adapted from (Frieman and Baric, 2008;Naqvi et al, 2020)) and share high degrees of peptide sequence homology (Supplemental Figure 1C). MHV-A59 utilizes the entry receptor CEACAM1, which is expressed on respiratory epithelium, but also on enterocytes, endothelial cells, monocytes, and neurons, as is the case with ACE2 (Compton et al, 1992;Godfraind et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19

Qing

Sharma

Hilliard

et al. 2020

Preprint

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Emerging clinical data demonstrates that COVID-19, the disease caused by SARS-CoV2, is a syndrome that variably affects nearly every organ system. Indeed, the clinical heterogeneity of COVID-19 ranges from relatively asymptomatic to severe disease with death resultant from multiple constellations of organ failures. In addition to genetics and host characteristics, it is likely that viral dissemination is a key determinant of disease manifestation. Given the complexity of disease expression, one major limitation in current animal models is the ability to capture this clinical heterogeneity due to technical limitations related to murinizing SARS-CoV2 or humanizing mice to render susceptible to infection. Here we describe a murine model of COVID-19 using respiratory infection with the native mouse betacoronavirus MHV-A59. We find that whereas high viral inoculums uniformly led to hypoxemic respiratory failure and death, lethal dose 50% (LD50) inoculums led to a recapitulation of most hallmark clinical features of COVID-19, including lymphocytopenias, heart and liver damage, and autonomic dysfunction. We find that extrapulmonary manifestations are due to viral metastasis and identify a critical role for type-I but not type-III interferons in preventing systemic viral dissemination. Early, but not late treatment with intrapulmonary type-I interferon, as well as convalescent serum, provided significant protection from lethality by limiting viral dissemination. We thus establish a Biosafety Level II model that may be a useful addition to the current pre-clinical animal models of COVID-19 for understanding disease pathogenesis and facilitating therapeutic development for human translation.

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“…In a month's time, SARS-CoV-2 has shown mutations in the ORF1ab polyprotein, surface glycoprotein and nucleocapsid phosphoprotein. The former two proteins have been shown to play an important role in the pathogenecity of the virus and the latter is responsible for the ssRNA packaging (6,26). All of the mutations which are non-synonymous incorporated nonpolar amino-acids in their protein (Table 3).…”

Section: Analyzing the Mutations In Sars-cov-2mentioning

confidence: 99%

“…has twelve functional open reading frames containing ~30,000 nucleotides which encodes for ~7096 residues long polyprotein (6). They represent all the structural and the non-structural proteins that help the virus to infect and survive in the host's cell (7).…”

Section: Introductionmentioning

confidence: 99%

An in-silico study on SARS-CoV-2: Its compatibility with human tRNA pool, and the polymorphism arising in a single lineage over a month

Victor

Das

Ghosh

2020

Preprint

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SARS-CoV-2 has caused a global pandemic that has costed enormous human lives in the recent past. The present study is an investigation of the viral codon adaptation, ORFs’ stability and tRNA co-adaptation with humans. We observed that for the codon usage bias in viral ssRNA, ORFs have near values of folding free energies and codon adaptation index with mRNAs of the human housekeeping CDS. However, the correlation between the stability of the ORFs in ssRNA and CAI is stronger than the mRNA stability and CAI of HKG, suggesting a greater expression capacity of SARS-CoV-2. Mutational analysis reflects polymorphism in the virus for ORF1ab, surface glycoprotein and nucleocapsid phosphoprotein ORFs. Non-synonymous mutations have shown non-polar substitutions. Out of the twelve mutations nine are for a higher t-RNA copy number. Viruses in general have high mutation rates. To understand the chances of survival for the mutated SARS-CoV-2 we did simulation for synonymous mutations. It resulted in 50% ORFs with higher stability than their native equivalents. Thus, considering only the synonymous mutations the virus can exhibit a lot of polymorphism. Collectively our data provides new insights for SARS-CoV-2 mutations and the human t-RNA compatibility.SignificanceSurvivability of SARS-CoV-2 in humans is essential for its spread. It has overlapping genes exhibiting a high codon optimization with humans even after a higher codon usage bias. They seem to possess cognizance for high copy number t-RNA (cognate or near-cognate) in humans, while mutating. Even though, it has been well established that native transcripts posses the highest stability, our in-silico studies show that SARS-CoV-2 under mutations give rise to ORFs with higher stability. These results significantly present the virus’s ability and the credibility of survival for the mutants. Despite its focus on a geographical location it explains the ongoing behavior of SARS-CoV-2 for a steady existence in humans as all the different lineages have a common origin. Wuhan, China.

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Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach

Cited by 843 publications

References 150 publications

SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells

SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells

Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19

An in-silico study on SARS-CoV-2: Its compatibility with human tRNA pool, and the polymorphism arising in a single lineage over a month

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