Institute of Immunobiology, Medical Research Center, Kantonsspital St. Gallen, St. Gallen, Switzerland.
Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
J Immunol. 2023 Mar 15;210(6):774-785. doi: 10.4049/jimmunol.2200533.
Hallmarks of life-threatening, coronavirus-induced disease include dysregulated antiviral immunity and immunopathological tissue injury. Nevertheless, the sampling of symptomatic patients overlooks the initial inflammatory sequela culminating in severe coronavirus-induced disease, leaving a fundamental gap in our understanding of the early mechanisms regulating anticoronavirus immunity and preservation of tissue integrity. In this study, we delineate the innate regulators controlling pulmonary infection using a natural mouse coronavirus. Within hours of infection, the cellular landscape of the lung was transcriptionally remodeled altering host metabolism, protein synthesis, and macrophage maturation. Genetic perturbation revealed that these transcriptional programs were type I IFN dependent and critically controlled both host cell survival and viral spread. Unrestricted viral replication overshooting protective IFN responses culminated in increased IL-1β and alarmin production and triggered compensatory neutrophilia, interstitial inflammation, and vascular injury. Thus, type I IFNs critically regulate early viral burden, which serves as an innate checkpoint determining the trajectory of coronavirus dissemination and immunopathology.
危及生命的冠状病毒诱导疾病的特征包括抗病毒免疫失调和免疫病理组织损伤。然而，对有症状患者的采样忽略了导致严重冠状病毒诱导疾病的初始炎症后遗症，这使得我们对调节抗病毒免疫和维持组织完整性的早期机制的理解存在根本空白。在这项研究中，我们使用天然小鼠冠状病毒描绘了控制肺部感染的先天调节因子。感染后数小时内，肺部的细胞景观在转录水平上进行了重塑，改变了宿主的代谢、蛋白质合成和巨噬细胞成熟。遗传干扰表明，这些转录程序依赖于 I 型 IFN，并严格控制宿主细胞的存活和病毒的传播。不受限制的病毒复制超过了保护性 IFN 反应，导致 IL-1β 和警报素的产生增加，并触发了代偿性嗜中性粒细胞、间质炎症和血管损伤。因此，I 型 IFN 严格调节早期病毒载量，作为一种先天检查点，决定冠状病毒传播和免疫病理学的轨迹。
