Université de Paris, Institut de Recherche Saint-Louis, Institut National de la Santé et de la Recherche Médicale U976, Hôpital Saint-Louis, Paris, France.
Université de Paris, Institut de Recherche Saint-Louis, Institut National de la Santé et de la Recherche Médicale U944, Centre National de la Recherche Scientifique 7212, Hôpital Saint-Louis, Paris, France.
J Exp Med. 2021 Apr 5;218(4). doi: 10.1084/jem.20201387.
Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.
几项研究分析了晚期严重 COVID-19 中的抗病毒免疫途径。然而，人们对 SARS-CoV-2 抗病毒免疫的初始步骤知之甚少。在这里，我们分离了原代 SARS-CoV-2 病毒株，并研究了它们与人浆细胞样树突状细胞（pDC）的相互作用，pDC 是抗病毒免疫的关键细胞。我们发现 pDC 不能被 SARS-CoV-2 有效感染。然而，它们在受到病毒刺激时能够有效地多样化为激活的 P1、P2 和 P3-pDC 效应亚群。它们表达 CD80、CD86、CCR7 和 OX40 配体的水平与流感病毒诱导的激活相似。它们迅速产生高水平的干扰素-α、干扰素-λ1、IL-6、IP-10 和 IL-8。氯喹可抑制 SARS-CoV-2 诱导的 pDC 活化的所有主要方面。从机制上讲，SARS-CoV-2 诱导的 pDC 活化严重依赖于 IRAK4 和 UNC93B1，这是使用基因缺陷患者的 pDC 确定的。总体而言，我们的数据表明，人类 pDC 可被 SARS-CoV-2 颗粒有效激活，因此可能有助于依赖 I 型 IFN 的 SARS-CoV-2 感染免疫。
