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Review 1: "The Unique ORF8 Protein From SARS-CoV-2 Binds to Human Dendritic Cells and Induces a Hyper-inflammatory Cytokine Storm"

This study demonstrates that neutralizing ORF8 may be a promising route of reducing immune hyperreactivity as a cause of severe disease. The claims presented in this work are reliable but could be strengthened through further statistical analysis.

Published onJul 15, 2022
Review 1: "The Unique ORF8 Protein From SARS-CoV-2 Binds to Human Dendritic Cells and Induces a Hyper-inflammatory Cytokine Storm"
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key-enterThis Pub is a Review of
The unique ORF8 protein from SARS-CoV-2 binds to human dendritic cells and induces a hyper-inflammatory cytokine storm

AbstractThe novel coronavirus pandemic, whose first outbreak was reported in December 2019 in Wuhan, China (COVID-19), is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Tissue damage caused by the virus leads to a strong immune response and activation of antigen-presenting cells, which can elicit acute respiratory distress syndrome (ARDS) characterized by the rapid onset of widespread inflammation, the so-called cytokine storm. In many viral infections the recruitment of monocytes into the lung and their differentiation to dendritic cells (DCs) are seen as a response to the viral infection. DCs are critical players in the development of the acute lung inflammation that causes ARDS. Here we focus on the interaction of the ORF8 protein, a specific SARS-CoV-2 open reading frame protein, with dendritic cells (DCs). We show that ORF8 binds to dendritic cells, causes a pre-maturation of differentiating DCs, and induces the secretion of multiple pro-inflammatory cytokines by these cells. In addition, we identified dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) as a possible interaction partner of ORF8 on dendritic cells. Blockade of ORF8 signaling leads to reduced production of IL-1β, IL-6, IL-12p70, TNF-α, MCP-1 (CCL2), and IL-10 by dendritic cells. Analysis of patient sera with high anti-ORF8 antibody titers showed that there was nearly no neutralization of the ORF8 protein and its function. Therefore, a neutralizing antibody that has the capacity of blocking the cytokine and chemokine response mediated by ORF8 protein might be an essential and novel additional step in the therapy of severe SARS-CoV-2 cases.

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.



Matthias Hamdorf et al report that ORF8 binds to human dendritic cells (DCs), causes and induces the secretion of multiple pro-inflammatory cytokines. This study reports novel and interesting findings but lacks statistical analysis. Below are the comments regarding the major problems of this submission:

1. The FACS, WB in figures 1, 2 and 6 lack statistical analysis. It is impossible to tell the significance to reach the conclusions.

2. Does ORF8 interact with macrophages?

3. The author claimed that ORF8 specifically binds to monocytes and DCs by detecting the FACS signal of recombinant ORF8 protein labeled with Atto488. However, the DCs and monocytes can uptake antigen in different mechanism. To reach the conclusion, they should exclude at least the phagocytosis with specifically inhibitor both in monocytes and DCs.

4. In figure 5, the cut-off is 0.4…how is the cut-off defined? Only IP-10 was found to be up-regulated in fig.5B and is very weak real word evidence to the conclusion of ORF8 inducing pro-inflammatory cytokine production.

5. The patients sera section is confusing… does high ORF8 antibody sera titer means high secretive ORF8 concentration?

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