Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), continues to cause significant morbidity and mortality in the ongoing global pandemic. Understanding the fundamental mechanisms that govern innate immune and inflammatory responses during SARS-CoV-2 infection is critical for developing effective therapeutic strategies. While IFN-based therapies are generally expected to be beneficial during viral infection, clinical trials in COVID-19 have shown limited efficacy and potential detrimental effects of IFN treatment during SARS-CoV-2 infection. However, the underlying mechanisms responsible for this failure remain unknown. In this study, we found that IFN induced ZBP1-mediated inflammatory cell death, PANoptosis, in human and murine macrophages and in the lungs of mice infected with β-coronaviruses, including SARS-CoV-2 and mouse hepatitis virus (MHV). In patients with COVID-19, expression of the innate immune sensor ZBP1 was increased in immune cells from those who succumbed to the disease compared with those who recovered, further suggesting a link between ZBP1 and pathology. In mice, IFN-β treatment following β-coronavirus infection increased lethality, and genetic deletion of Zbp1 or its Zα domain suppressed cell death and protected the mice from IFN-mediated lethality during β-coronavirus infection. Overall, our results identify that ZBP1 induced during coronavirus infection limits the efficacy of IFN therapy by driving inflammatory cell death and lethality. Therefore, inhibiting ZBP1 activity may improve the efficacy of IFN therapy, paving the way for the development of new and critically needed therapeutics for COVID-19 as well as other infections and inflammatory conditions where IFN-mediated cell death and pathology occur.

中文翻译：

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冠状病毒感染期间 ZBP1 依赖性炎症细胞死亡、全凋亡和细胞因子风暴破坏 IFN 治疗效果


严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是导致 2019 年冠状病毒病 (COVID-19) 的病毒，在当前的全球大流行中继续造成显着的发病率和死亡率。了解 SARS-CoV-2 感染期间控制先天免疫和炎症反应的基本机制对于制定有效的治疗策略至关重要。虽然基于 IFN 的疗法通常被认为在病毒感染期间是有益的，但 COVID-19 的临床试验表明，在 SARS-CoV-2 感染期间，IFN 治疗的疗效有限，并且存在潜在的有害影响。然而，造成这种失败的根本机制仍然未知。在这项研究中，我们发现 IFN 在人类和小鼠巨噬细胞以及感染 β-冠状病毒（包括 SARS-CoV-2 和小鼠肝炎病毒 (MHV)）的小鼠肺部中诱导 ZBP1 介导的炎症细胞死亡（PANoptosis）。在 COVID-19 患者中，先天免疫传感器的表达ZBP1与康复者相比，死于该疾病的人的免疫细胞有所增加，进一步表明 ZBP1 与病理学之间存在联系。在小鼠中，β-冠状病毒感染后的 IFN-β 治疗增加了致死率，并且基因缺失Zbp1或其 Zα 结构域抑制细胞死亡，并保护小鼠在 β-冠状病毒感染期间免受 IFN 介导的致死。总体而言，我们的结果表明，冠状病毒感染期间诱导的 ZBP1 通过驱动炎症细胞死亡和致死来限制 IFN 治疗的疗效。 因此，抑制 ZBP1 活性可能会提高 IFN 疗法的疗效，为开发新的且急需的疗法铺平道路，以治疗 COVID-19 以及发生 IFN 介导的细胞死亡和病理的其他感染和炎症状况。