SARS-CoV-2 ORF8 modulates lung inflammation and clinical disease progression
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- Evaluated articles (Rapid Reviews Infectious Diseases)
Abstract
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.
Significance
Since its emergence in 2019, SARS-CoV-2 has accrued mutations throughout its 30kb genome. Of particular interest are the mutations present in the ORF8 protein, which occur in every major variant. The precise function and impact of this protein on disease severity and pathogenesis remains understudies. Our studies reveal that the ORF8 protein modulates the immune response by impacting macrophage infiltration into the lungs. Additionally, we have shown that the ORF8 protein of SARS-CoV-2 has accrued mutations throughout its evolution that lead to a loss of function phenotype in this protein. Our work reveals that the ORF8 protein of SARS-CoV-2 contributes significantly to disease progression through modulation of the inflammatory response.
Article activity feed
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Marlene Bouvier
Review 3: "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.
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Jack Chen
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.
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Yee-Joo Tan, Kah Man Lai
Review 1: "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.
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Strength of evidence
Reviewers: Y Tan & K M Lai (National University of Singapore) | 📗📗📗📗◻️
J Chen (University of Alaska Fairbanks) | 📗📗📗📗◻️
M Bouvier (University of Illinois) | 📗📗📗📗◻️ -
This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/8429231.
Does the introduction explain the objective of the research presented in the preprint? Yes The introduction first provides context on the background of COVID-19 and the SARS-CoV-2 virus. The authors explain the general functions and characteristics of the ORF8 accessory protein. According to the authors, their previous work on accessory protein deletion viruses for SARS-CoV-2 revealed that an ORF8 deletion virus resulted in more lung inflammation compared to a clinical isolate. The authors explain that the objective of their research is to further investigate and characterize the impact of …This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/8429231.
Does the introduction explain the objective of the research presented in the preprint? Yes The introduction first provides context on the background of COVID-19 and the SARS-CoV-2 virus. The authors explain the general functions and characteristics of the ORF8 accessory protein. According to the authors, their previous work on accessory protein deletion viruses for SARS-CoV-2 revealed that an ORF8 deletion virus resulted in more lung inflammation compared to a clinical isolate. The authors explain that the objective of their research is to further investigate and characterize the impact of ORF8 in clinical disease progression.Are the methods well-suited for this research? Highly appropriate The methods are very well suited for this research. The authors infect K18-hACE2 mice with WA-1AORF8, following biosafety approval.Are the conclusions supported by the data? Highly supported The conclusions are strongly supported by the data. The researchers present data that reveals that mice infected with WA-1AORF8 demonstrated increased levels of lung inflammation compared to mice with wildtype virus.Are the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear The tables and graphs allow the data from the results to be visualized and support the conclusions made.How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearlyIs the preprint likely to advance academic knowledge? Highly likely The preprint is very likely to generate further studies on the topic of ORF8 in SARS-CoV-2, which is still rather elusive. The findings in this paper also confirm and extend previous research done by the researchers.Would it benefit from language editing? NoWould you recommend this preprint to others? Yes, it's of high qualityIs it ready for attention from an editor, publisher or broader audience? Yes, as it is The paper presents useful findings on a topic that is not well-studied. The paper provides valuable data and information that would be beneficial to spread to a larger audience. It could also generate further discussions on this topic.Competing interestsThe author declares that they have no competing interests.
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This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/8403575.
Does the introduction explain the objective of the research presented in the preprint? Yes The preprint gives a brief introduction on the COVID-19 pandemic before diving into a short, but comprehensive characteristic description of the SARS-CoV-2 virus--mainly, its accessory proteins. Then, using prior knowledge of the ORF8's behavior in SARS-CoV-1, the preprint applies its understanding to form hypotheses on SARS-CoV-2's ORF8's function. The preprint states that prior work has shown that an ORF8 deletion virus resulted in increased lung inflammation, but to further characterize the impact …This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/8403575.
Does the introduction explain the objective of the research presented in the preprint? Yes The preprint gives a brief introduction on the COVID-19 pandemic before diving into a short, but comprehensive characteristic description of the SARS-CoV-2 virus--mainly, its accessory proteins. Then, using prior knowledge of the ORF8's behavior in SARS-CoV-1, the preprint applies its understanding to form hypotheses on SARS-CoV-2's ORF8's function. The preprint states that prior work has shown that an ORF8 deletion virus resulted in increased lung inflammation, but to further characterize the impact of ORF8, another study was conducted where the result ultimately shows that an absence of ORF8 causes increased immune cell infiltration. Therefore, the preprint provides a seamless segue into explaining its objective at the end of the introduction.Are the methods well-suited for this research? Highly appropriate The preprint notes how all virus experiments and recombinant virus creation was approved by the Institutional Biosafety Committee at The University of Maryland, Baltimore. Additionally, each method under the methods section would state where materials were obtained from or from what company lab kits were used from. For processes that required multiple calculation-based steps, the preprint also provided these values, allowing for replication.Are the conclusions supported by the data? Highly supportedAre the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear Each of the provided figures or tables included in the preprint came with their own legend, which were all very descriptive.How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Somewhat clearly The paper's discussion section was highly detailed in terms of explaining and interpreting their findings. However, the preprint only gives a brief nod to potential next steps by explaining how they hope to characterize differences in inflammation in the two different strains of the SARS-CoV-2 virus through further studies. No additional depth was provided in what they hope to see/hypothesize/detailed reasons for conducting further analysis.Is the preprint likely to advance academic knowledge? Highly likelyWould it benefit from language editing? No The preprint did not have grammatical errors or unclear expressions.Would you recommend this preprint to others? Yes, it's of high qualityIs it ready for attention from an editor, publisher or broader audience? Yes, as it is ORF8 is not a commonly researched protein based on studies that have conducted research on the SARS-CoV-2 virus. The paper seems highly knowledgeable in the information and results it comes to that it would benefit from attention from a broader audience as it offers valuable and unique information.Competing interestsThe author declares that they have no competing interests.
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