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Review 2: "SARS-CoV-2 ORF8 Modulates Lung Inflammation and Clinical Disease Progression"

Overall, reviewers rated this preprint as reliable, though further validation and mechanistic dissection of ORF8 would be beneficial.

Published onOct 13, 2023
Review 2: "SARS-CoV-2 ORF8 Modulates Lung Inflammation and Clinical Disease Progression"
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key-enterThis Pub is a Review of
SARS-CoV-2 ORF8 modulates lung inflammation and clinical disease progression
SARS-CoV-2 ORF8 modulates lung inflammation and clinical disease progression

The virus severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, is the causative agent of the current COVID-19 pandemic. It possesses a large 30 kilobase (kb) genome that encodes structural, non-structural, and accessory proteins. Although not necessary to cause disease, these accessory proteins are known to influence viral replication and pathogenesis. Through the synthesis of novel infectious clones of SARS-CoV-2 that lack one or more of the accessory proteins of the virus, we have found that one of these accessory proteins, ORF8, is critical for the modulation of the host inflammatory response. Mice infected with a SARS-CoV-2 virus lacking ORF8 exhibit increased weight loss and exacerbated macrophage infiltration into the lungs. Additionally, infection of mice with recombinant SARS-CoV-2 viruses encoding ORF8 mutations found in variants of concern reveal that naturally occurring mutations in this protein influence disease severity. Our studies with a virus lacking this ORF8 protein and viruses possessing naturally occurring point mutations in this protein demonstrate that this protein impacts pathogenesis.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.


Review: In this manuscript, McGrath, et al. studied the SARS-CoV-2 ORF8 gene on modulating clinical disease progression and concluded that SARS-CoV-2 lacking this ORF8 protein and virus possessing naturally occurring point mutations impacts pathogenesis. Overall, their results are technically sound and conclusion is convincing.

 Major comments:

  1. In “Introduction” part, line 70, the authors mentioned that “As every variant that has emerged since B.1.1.7 in late 2020 possesses either one or more ORF8 mutations……”, this may not be true. I suggest the authors to include an analysis of all SARS-CoV-2 genome data published on GISAID on the percentage of all virus genomes bearing ORF8 mutation(s). Also, the authors are suggested to include some publications on virus genome analysis related to ORF8 mutations such as:

    Identification of a novel SARS-CoV-2 variant with a truncated protein in ORF8 gene by next generation sequencing. S DeRonde, H Deuling, J Parker, J Chen. Scientific reports 12 (1), 4631

  2. Line 72 mentioned that “synthesizing recombinant WA-1 virus containing variant ORF8 genes of B.1.1.7, B.1.351, and P.1…” but in “Materials and Methods”, only construction of ORF8 single in B.1.1.7 and P.1 Variants were mentioned. If B.1.351 has identical sequences with either of the above two variants, the authors need to indicate that.

  3. In “Materials and Methods”, the authors need to present whole genomic sequencing data of their constructs to prove there is no additional mutations/deletions other than the ORF8 genes, as large genomic fragment manipulated in yeast/bacteria are prone to mutation/deletion.

  4. Line 233, the background of WA-1 needs a brief introduction or at least a citation of the authors’ previous work.

  5. Line 235, “SARS-CoV-2 ORF8 has been proposed to have several functions”, this statement needs some literature citation.

  6. Line 308, “we noticed an increase in the incidence of naturally occurring mutations in the ORF8 protein…”, this needs statistic data support or reference cited.

  7. Current Omicron variants seems to be less virulent and severe, yet Omicron variants bear mutated ORF8, how to explain this controverse.

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