Cornea Lab Experimental Ophthalmology, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany.
Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA.
J Mol Cell Biol. 2024 Apr 4;15(10). doi: 10.1093/jmcb/mjad062.
The novel coronavirus pandemic, first reported in December 2019, was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection 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 response to viral infections, monocytes are recruited into the lung and subsequently differentiate into dendritic cells (DCs). DCs are critical players in the development of acute lung inflammation that causes ARDS. Here, we focus on the interaction of a specific SARS-CoV-2 open reading frame protein, ORF8, with DCs. We show that ORF8 binds to DCs, causes pre-maturation of differentiating DCs, and induces the secretion of multiple proinflammatory cytokines by these cells. In addition, we identified DC-SIGN as a possible interaction partner of ORF8 on DCs. Blockade of ORF8 leads to reduced production of IL-1β, IL-6, IL-12p70, TNF-α, MCP-1 (also named CCL2), and IL-10 by DCs. Therefore, a neutralizing antibody blocking the ORF8-mediated cytokine and chemokine response could be an improved therapeutic strategy against SARS-CoV-2.
新型冠状病毒疫情于 2019 年 12 月首次报告，由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起。SARS-CoV-2 感染会导致强烈的免疫反应和抗原呈递细胞的激活，从而引发以广泛炎症迅速发作为特征的急性呼吸窘迫综合征（ARDS），即所谓的细胞因子风暴。针对病毒感染，单核细胞被募集到肺部，随后分化为树突状细胞（DCs）。DCs 是导致 ARDS 的急性肺炎症发展的关键参与者。在这里，我们重点关注特定的 SARS-CoV-2 开放阅读框蛋白 ORF8 与 DCs 的相互作用。我们表明 ORF8 与 DCs 结合，导致分化中的 DCs 的预成熟，并诱导这些细胞分泌多种促炎细胞因子。此外，我们鉴定了 DC-SIGN 作为 ORF8 在 DCs 上的可能相互作用伙伴。阻断 ORF8 会导致 DC 产生的 IL-1β、IL-6、IL-12p70、TNF-α、MCP-1（也称为 CCL2）和 IL-10 减少。因此，阻断 ORF8 介导的细胞因子和趋化因子反应的中和抗体可能是对抗 SARS-CoV-2 的改进治疗策略。
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