Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Graduate Programs in Biomedical and Biological Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
PLoS Pathog. 2023 Mar 24;19(3):e1011240. doi: 10.1371/journal.ppat.1011240. eCollection 2023 Mar.
One of the major pathogenesis mechanisms of SARS-CoV-2 is its potent suppression of innate immunity, including blocking the production of type I interferons. However, it is unknown whether and how the virus interacts with different innate-like T cells, including NKT, MAIT and γδ T cells. Here we reported that upon SARS-CoV-2 infection, invariant NKT (iNKT) cells rapidly trafficked to infected lung tissues from the periphery. We discovered that the envelope (E) protein of SARS-CoV-2 efficiently down-regulated the cell surface expression of the antigen-presenting molecule, CD1d, to suppress the function of iNKT cells. E protein is a small membrane protein and a viroporin that plays important roles in virion packaging and envelopment during viral morphogenesis. We showed that the transmembrane domain of E protein was responsible for suppressing CD1d expression by specifically reducing the level of mature, post-ER forms of CD1d, suggesting that it suppressed the trafficking of CD1d proteins and led to their degradation. Point mutations demonstrated that the putative ion channel function was required for suppression of CD1d expression and inhibition of the ion channel function using small chemicals rescued the CD1d expression. Importantly, we discovered that among seven human coronaviruses, only E proteins from highly pathogenic coronaviruses including SARS-CoV-2, SARS-CoV and MERS suppressed CD1d expression, whereas the E proteins of human common cold coronaviruses, HCoV-OC43, HCoV-229E, HCoV-NL63 and HCoV-HKU1, did not. These results suggested that E protein-mediated evasion of NKT cell function was likely an important pathogenesis factor, enhancing the virulence of these highly pathogenic coronaviruses. Remarkably, activation of iNKT cells with their glycolipid ligands, both prophylactically and therapeutically, overcame the putative viral immune evasion, significantly mitigated viral pathogenesis and improved host survival in mice. Our results suggested a novel NKT cell-based anti-SARS-CoV-2 therapeutic approach.
SARS-CoV-2 的主要发病机制之一是其强烈抑制先天免疫，包括阻断 I 型干扰素的产生。然而，目前尚不清楚病毒是否以及如何与不同的先天样 T 细胞相互作用，包括 NKT、MAIT 和 γδ T 细胞。在这里，我们报道了在 SARS-CoV-2 感染后，不变自然杀伤 T(iNKT)细胞从外周迅速迁移到受感染的肺组织。我们发现，SARS-CoV-2 的包膜(E)蛋白有效地下调了抗原呈递分子 CD1d 的细胞表面表达，从而抑制了 iNKT 细胞的功能。E 蛋白是一种小的膜蛋白和病毒孔蛋白，在病毒形态发生过程中对病毒粒子的包装和包裹起着重要作用。我们表明，E 蛋白的跨膜结构域负责通过特异性降低成熟、内质网后形式的 CD1d 水平来抑制 CD1d 表达，这表明它抑制了 CD1d 蛋白的转运，并导致其降解。点突变表明，假定的离子通道功能对于抑制 CD1d 表达是必需的，并且使用小分子抑制离子通道功能可挽救 CD1d 表达。重要的是，我们发现，在七种人类冠状病毒中，只有 SARS-CoV-2、SARS-CoV 和 MERS 等高致病性冠状病毒的 E 蛋白能够抑制 CD1d 表达，而人类普通感冒冠状病毒，HCoV-OC43、HCoV-229E、HCoV-NL63 和 HCoV-HKU1 的 E 蛋白则不能。这些结果表明，E 蛋白介导的 NKT 细胞功能逃避可能是一个重要的发病机制因素，增强了这些高致病性冠状病毒的毒力。值得注意的是，用其糖脂配体预防性和治疗性地激活 iNKT 细胞，克服了病毒的免疫逃避，显著减轻了病毒发病机制，并提高了小鼠的存活率。我们的研究结果提出了一种新的基于 NKT 细胞的抗 SARS-CoV-2 治疗方法。
