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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.

Published onOct 13, 2023
Review 1: "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
Description

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.

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Review: There are mutations in multiple viral proteins of SARS-CoV-2 as the virus evolves to yield variants of concern (VOC). One of the viral proteins is known as ORF8 and it has acquired mutations which have been shown to affect viral pathogenesis in a mouse model of infection. Mice infected with a recombinant virus lacking ORF8 was found to cause higher levels of inflammation in the lungs than wild-type mice, indicating the ORF8 plays an important role in viral pathogenesis. Furthermore, recombinant viruses containing mutated ORF8 found in VOCs were analyzed in mice, and the results show that the mutations in ORF8 occurring throughout the evolution of SARS-CoV-2 affects its function and could influence pathogenesis. 

The present work reported the role of SARS-CoV-2 accessory protein, ORF8 in modulating host inflammatory response by using infection of hACE2-k18 mice. As compared to clinical isolate WA-1, infection of mice with recombinant SARS-CoV-2 lacking ORF8 led to increased weight loss and increased lung inflammation. This is consistent with their previous publication as well as those published by others. Transcriptomic analysis revealed that WA-1ΔORF8 enhanced upregulation of neutrophil and macrophage signalling pathways. In accordance with transcriptomic finding, WA-1ΔORF8 infection led to higher population of macrophages in the lungs. Importantly, they performed a detailed study on the role of ORF8 on lung inflammation by generating recombinant SARS-CoV-2 containing naturally occurring ORF8 mutations found in several VOCs. It is suggested that the mutations in ORF8 occurring throughout the evolution of SARS-CoV-2 affects its function and could influence pathogenesis. Thus, the present work provides novel evidence on the importance of ORF8 in modulating inflammatory response and contributing to disease progression. 

Suggestions:

  1. It will be useful to discuss the publications of ORF8 in relation to different animal models. For example, a study using neonatal mice suggests that ORF8 contributes to transmissibility (Rodriguez-Rodriguez, B.A., Ciabattoni, G.O., Duerr, R. et al. A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8. Nat Commun 14, 3026 (2023). https://doi.org/10.1038/s41467-023-38783-0)

  2. With regards to VOCs, is there any correlation between the mutations in ORF8 with clinical outcome in patients? If not, what are the possible reasons?

  3. How does the mutations in ORF8 affect its functions like those reported by others and cited by the authors in “Introduction”? It will also be useful to determine if the mutations affect the differentially expressed genes in WA-1 and WA-1ΔORF8 infection identified in this study.

  4. How does the mutations in ORF8 affect macrophage pathways? Is it correlated to lung inflammation? 

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