Department of Experimental Immunology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.
Amsterdam institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands.
PLoS Pathog. 2023 Oct 16;19(10):e1011735. doi: 10.1371/journal.ppat.1011735. eCollection 2023 Oct.
SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with bacteria during severe COVID-19 often cause pneumonia, bacteremia and sepsis. Aberrant immune responses might underlie increased sensitivity to bacteria during COVID-19 but the mechanisms remain unclear. Here we investigated whether SARS-CoV-2 directly suppresses immune responses to bacteria. We studied the functionality of human dendritic cells (DCs) towards a variety of bacterial triggers after exposure to SARS-CoV-2 Spike (S) protein and SARS-CoV-2 primary isolate (hCoV-19/Italy). Notably, pre-exposure of DCs to either SARS-CoV-2 S protein or a SARS-CoV-2 isolate led to reduced type I interferon (IFN) and cytokine responses in response to Toll-like receptor (TLR)4 agonist lipopolysaccharide (LPS), whereas other TLR agonists were not affected. SARS-CoV-2 S protein interacted with the C-type lectin receptor DC-SIGN and, notably, blocking DC-SIGN with antibodies restored type I IFN and cytokine responses to LPS. Moreover, blocking the kinase Raf-1 by a small molecule inhibitor restored immune responses to LPS. These results suggest that SARS-CoV-2 modulates DC function upon TLR4 triggering via DC-SIGN-induced Raf-1 pathway. These data imply that SARS-CoV-2 actively suppresses DC function via DC-SIGN, which might account for the higher mortality rates observed in patients with COVID-19 and bacterial superinfections.
SARS-CoV-2 导致 COVID-19，这是一种具有从轻度感冒到严重肺炎、炎症甚至死亡等症状的传染病。虽然强烈的炎症反应是导致发病率和死亡率的主要因素，但在严重 COVID-19 期间，细菌的合并感染常导致肺炎、菌血症和败血症。COVID-19 期间对细菌的敏感性增加可能是异常免疫反应的结果，但机制尚不清楚。在这里，我们研究了 SARS-CoV-2 是否直接抑制对细菌的免疫反应。我们研究了人类树突状细胞（DC）在暴露于 SARS-CoV-2 刺突（S）蛋白和 SARS-CoV-2 原始分离株（hCoV-19/意大利）后对各种细菌触发物的功能。值得注意的是，DC 预先暴露于 SARS-CoV-2 S 蛋白或 SARS-CoV-2 分离株会导致对 Toll 样受体（TLR）4 激动剂脂多糖（LPS）的 I 型干扰素（IFN）和细胞因子反应减少，而其他 TLR 激动剂不受影响。SARS-CoV-2 S 蛋白与 C 型凝集素受体 DC-SIGN 相互作用，值得注意的是，用抗体阻断 DC-SIGN 可恢复对 LPS 的 I 型 IFN 和细胞因子反应。此外，用小分子抑制剂阻断激酶 Raf-1 可恢复对 LPS 的免疫反应。这些结果表明，SARS-CoV-2 通过 DC-SIGN 诱导的 Raf-1 途径在 TLR4 触发后调节 DC 功能。这些数据表明，SARS-CoV-2 通过 DC-SIGN 主动抑制 DC 功能，这可能是 COVID-19 患者和细菌合并感染中观察到更高死亡率的原因。
