A Conservative Replacement in the Transmembrane Domain of SARS-CoV-2 ORF7a as a Putative Risk Factor in COVID-19

Lobiuc, Andrei; Șterbuleac, Daniel; Sturdza, Olga; Dimian, Mihai; Covașă, Mihai

doi:10.3390/biology10121276

Cited by 12 publications

(15 citation statements)

References 40 publications

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“…The association of ORF7a: P45L mutation with disease severity in Uzbekistan, reported for the first time herein ( Table 10 ), is in concordance with previous research, that the stabilizing mutation in the ORF7a of a SARS-CoV-2 was associated with the increased severity and lethality in a group of Romanian patients, despite a lower viral copy number and a lower number of associated comorbidities [ 38 ].…”

Section: Discussionsupporting

confidence: 91%

Genome sequence diversity of SARS-CoV-2 obtained from clinical samples in Uzbekistan

Абдуллаев¹,

Abdurakhimov²,

Mirakbarova³

et al. 2022

PLoS ONE

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Tracking temporal and spatial genomic changes and evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are among the most urgent research topics worldwide, which help to elucidate the coronavirus disease 2019 (COVID-19) pathogenesis and the effect of deleterious variants. Our current study concentrates genetic diversity of SARS-CoV-2 variants in Uzbekistan and their associations with COVID-19 severity. Thirty-nine whole genome sequences (WGS) of SARS-CoV-2 isolated from PCR-positive patients from Tashkent, Uzbekistan for the period of July-August 2021, were generated and further subjected to further genomic analysis. Genome-wide annotations of clinical isolates from our study have revealed a total of 223 nucleotide-level variations including SNPs and 34 deletions at different positions throughout the entire genome of SARS-CoV-2. These changes included two novel mutations at the Nonstructural protein (Nsp) 13: A85P and Nsp12: Y479N, which were unreported previously. There were two groups of co-occurred substitution patterns: the missense mutations in the Spike (S): D614G, Open Reading Frame (ORF) 1b: P314L, Nsp3: F924, 5`UTR:C241T; Nsp3:P2046L and Nsp3:P2287S, and the synonymous mutations in the Nsp4:D2907 (C8986T), Nsp6:T3646A and Nsp14:A1918V regions, respectively. The “Nextstrain” clustered the largest number of SARS-CoV-2 strains into the Delta clade (n = 32; 82%), followed by two Alpha-originated (n = 4; 10,3%) and 20A (n = 3; 7,7%) clades. Geographically the Delta clade sample sequences were grouped into several clusters with the SARS-CoV genotypes from Russia, Denmark, USA, Egypt and Bangladesh. Phylogenetically, the Delta isolates in our study belong to the two main subclades 21A (56%) and 21J (44%). We found that females were more affected by 21A, whereas males by 21J variant (χ2 = 4.57; p ≤ 0.05, n = 32). The amino acid substitution ORF7a:P45L in the Delta isolates found to be significantly associated with disease severity. In conclusion, this study evidenced that Identified novel substitutions Nsp13: A85P and Nsp12: Y479N, have a destabilizing effect, while missense substitution ORF7a: P45L significantly associated with disease severity.

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Section: Discussionsupporting

confidence: 91%

Genome sequence diversity of SARS-CoV-2 obtained from clinical samples in Uzbekistan

Абдуллаев¹,

Abdurakhimov²,

Mirakbarova³

et al. 2022

PLoS ONE

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“…In addition, it died out in the immunocompetent population 1.5 months after it was detected (39). Another study identified a mutation in the transmembrane domain of ORF7a that improved its stability and caused severe infection despite low viral loads (40) although the mechanism behind this has not been determined. A mouse model of COVID19 using DORF7a rSARS-CoV-2 showed that this virus had a replication defect in vitro, was cleared more efficiently from the nasal turbines than intact virus, and lung lesions caused by it were also resolved sooner (28).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to downregulate MHC-I surface expression

Arshad

Laurent-Rolle

Ahmed

et al. 2022

Preprint

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Major histocompatibility complex class I (MHC-I) molecules, which are dimers of a glycosylated polymorphic transmembrane heavy chain and the small protein β2-microglobulin (β2m), bind peptides in the endoplasmic reticulum that are generated by the cytosolic turnover of cellular proteins. In virus-infected cells these peptides may include those derived from viral proteins. Peptide-MHC-I complexes then traffic through the secretory pathway and are displayed at the cell surface where those containing viral peptides can be detected by CD8+ T lymphocytes that kill infected cells. Many viruses enhance their in vivo survival by encoding genes that downregulate MHC-I expression to avoid CD8+ T cell recognition. Here we report that two accessory proteins encoded by SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, downregulate MHC-I expression using distinct mechanisms. One, ORF3a, a viroporin, reduces global trafficking of proteins, including MHC-I, through the secretory pathway. The second, ORF7a, interacts specifically with the MHC-I heavy chain, acting as a molecular mimic of β2m to inhibit its association. This slows the exit of properly assembled MHC-I molecules from the endoplasmic reticulum. We demonstrate that ORF7a reduces antigen presentation by the human MHC-I allele HLA-A*02:01. Thus, both ORF3a and ORF7a act post-translationally in the secretory pathway to lower surface MHC-I expression, with ORF7a exhibiting a novel and specific mechanism that allows immune evasion by SARS-CoV-2.Significance StatementViruses may down-regulate MHC class I expression on infected cells to avoid elimination by cytotoxic T cells. We report that the accessory proteins ORF7a and ORF3a of SARS-CoV-2 mediate this function and delineate the two distinct mechanisms involved. While ORF3a inhibits global protein trafficking to the cell surface, ORF7a acts specifically on MHC-I by competing with β2m for binding to the MHC-I heavy chain. This is the first account of molecular mimicry of β2m as a viral mechanism of MHC-I down-regulation to facilitate immune evasion.

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“…In the case of the 44 patients described here, the AASs S81P occurred twice in P14 and P22 (4.5%), and the A105V, which occurred in P9, has been characterized before. In a 62-patient Romanian cohort, Lobiuc et al (2021) showed that 27.5% were infected with the A105V AAS, and they experienced a twofold higher death rate than others without A105V. The researchers then did a bioinformatic analysis of this change and predicted an increased stability by allosteric effects (Lobiuc et al, 2021).…”

Section: Orf7amentioning

confidence: 99%

“…In a 62-patient Romanian cohort, Lobiuc et al (2021) showed that 27.5% were infected with the A105V AAS, and they experienced a twofold higher death rate than others without A105V. The researchers then did a bioinformatic analysis of this change and predicted an increased stability by allosteric effects (Lobiuc et al, 2021).…”

Section: Orf7amentioning

confidence: 99%

Identifying Markers of Emerging SARS-CoV-2 Variants in Patients With Secondary Immunodeficiency

Markarian

Galli²,

Patel³

et al. 2022

Front. Microbiol.

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Since the end of 2019, the world has been challenged by the coronavirus disease 2019 (COVID-19) pandemic. With COVID-19 cases rising globally, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, resulting in the emergence of variants of interest (VOI) and of concern (VOC). Of the hundreds of millions infected, immunodeficient patients are one of the vulnerable cohorts that are most susceptible to this virus. These individuals include those with preexisting health conditions and/or those undergoing immunosuppressive treatment (secondary immunodeficiency). In these cases, several researchers have reported chronic infections in the presence of anti-COVID-19 treatments that may potentially lead to the evolution of the virus within the host. Such variations occurred in a variety of viral proteins, including key structural ones involved in pathogenesis such as spike proteins. Tracking and comparing such mutations with those arisen in the general population may provide information about functional sites within the SARS-CoV-2 genome. In this study, we reviewed the current literature regarding the specific features of SARS-CoV-2 evolution in immunocompromised patients and identified recurrent de novo amino acid changes in virus isolates of these patients that can potentially play an important role in SARS-CoV-2 pathogenesis and evolution.

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A Conservative Replacement in the Transmembrane Domain of SARS-CoV-2 ORF7a as a Putative Risk Factor in COVID-19

Cited by 12 publications

References 40 publications

Genome sequence diversity of SARS-CoV-2 obtained from clinical samples in Uzbekistan

Genome sequence diversity of SARS-CoV-2 obtained from clinical samples in Uzbekistan

SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to downregulate MHC-I surface expression

Identifying Markers of Emerging SARS-CoV-2 Variants in Patients With Secondary Immunodeficiency

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