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Review 2: "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 2: "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.



This article by Hamdorf et al is an original contribution to understand the mechanism by which ORF8 contributes to the generation of the characteristic cytokine storm of SARS-CoV-2 infection. It experimentally confirms the already suspected functions of ORF8 as a secreted protein that can produce a whole series of long-term secondary effects in patients infected with this virus. The experimental model used makes clear several essential aspects of the generation of the exacerbated immune response observed in patients with COVID-19:

1) ORF8 binds specifically to monocytes and DCs and is lacking the property to induce DC differentiation;

2) ORF8 induces a strong cytokine storm during dendritic cell differentiation;

3) polyclonal rabbit antibody against ORF8 is able to strongly reduce the binding of ORF8 and the humoral immune response of dendritic cells.

Thus, these experimental results strongly support the role of ORF8 as a central node in the network of molecular processes that determine the deregulated immune response of patients with COVID19, and in the generation of the long-lasting secondary symptoms observed in these patients. These results also suggest that ORF8 should be considered as a central target for the design of therapeutic drugs to combat this virus. In conclusion, this preprint sheds important new clues to clarify the role that this accessory protein ORF8 may have in generating the variety of sequelae observed in patients infected with this virus. Therefore, it is necessary in the development of new drugs to specifically neutralize this protein as suggested by the authors.

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