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The Unique ORF8 Protein From SARS-CoV-2 Binds to Human Dendritic Cells and Induces a Hyper-Inflammatory Cytokine Storm
56 Pages Posted: 15 Dec 2021
More...Abstract
The 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. Patients with a high anti-ORF8 antibody titer show significantly elevated interferon-gamma induced protein 10 (IP-10, CXCL10) levels in their serum. 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.
Funding Information: This work is supported by German Research Foundation (DFG) research unit FOR2240 (www.FOR2240.de) BO4489/1-1, BO4489/1-2, BO4489/3-1 (F.B.) Cu 47/9-1 and 12-1 and CMMC Cologne (FB, CC, M.K.); German Research Foundation (DFG) research unit - FOR 2722 (M.K.)
Declaration of Interests: The authors do not have any conflicting financial interests.
Ethics Approval Statement: Ethical clearance for the use of human material was obtained from the ethical review committee of the university hospital Cologne (N°11-339).
Keywords: COVID-19, SARS-CoV-2, ORF8, cytokine storm, dendritic cells
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