Abstract：
COVID-19 syndrome is characterized by acute lung injury, hypoxemic respiratory failure, and high mortality. Alveolar type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and other members of the β-coronavirus genus induce an endoplasmic reticulum (ER) stress response in vitro; however, the consequences for host AT2 cell function in vivo are less understood. To study this, two murine models of coronavirus infection were used-mouse hepatitis virus-1 (MHV-1) in A/J mice and a mouse-adapted SARS-CoV-2 strain. MHV-1-infected mice exhibited dose-dependent weight loss with histological evidence of distal lung injury accompanied by elevated bronchoalveolar lavage fluid (BALF) cell counts and total protein. AT2 cells showed evidence of both viral infection and increased BIP/GRP78 expression, consistent with activation of the unfolded protein response (UPR). The AT2 UPR included increased inositol-requiring enzyme 1α (IRE1α) signaling and a biphasic response in PKR-like ER kinase (PERK) signaling accompanied by marked reductions in AT2 and BALF surfactant protein (SP-B and SP-C) content, increases in surfactant surface tension, and emergence of a reprogrammed epithelial cell population (Krt8+ and Cldn4+). The loss of a homeostatic AT2 cell state was attenuated by treatment with the IRE1α inhibitor OPK-711. As a proof-of-concept, C57BL6 mice infected with mouse-adapted SARS-CoV-2 demonstrated similar lung injury and evidence of disrupted surfactant homeostasis. We conclude that lung injury from β-coronavirus infection results from an aberrant host response, activating multiple AT2 UPR stress pathways, altering surfactant metabolism/function, and changing AT2 cell state, offering a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and acute respiratory failure.NEW & NOTEWORTHY COVID-19 syndrome is characterized by hypoxemic respiratory failure and high mortality. In this report, we use two murine models to show that β-coronavirus infection produces acute lung injury, which results from an aberrant host response, activating multiple epithelial endoplasmic reticular stress pathways, disrupting pulmonary surfactant metabolism and function, and forcing emergence of an aberrant epithelial transition state. Our results offer a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and respiratory failure.
摘要：
COVID-19综合征以急性肺损伤为特征,低氧性呼吸衰竭，和高死亡率。肺泡2型（AT2）细胞对于气体交换至关重要，修复,和远端肺上皮的再生。我们已经证明了病原体，SARS-CoV-2和其他β-冠状病毒属成员在体外诱导ER应激反应，然而，对宿主AT2在体内功能的影响知之甚少。为了研究这个，使用了两种小鼠冠状病毒感染模型-A/J小鼠中的小鼠肝炎病毒1（MHV-1）和小鼠适应SARS-CoV-2株。MHV-1感染的小鼠表现出剂量依赖性体重减轻，具有远端肺损伤的组织学证据，伴有支气管肺泡灌洗液（BALF）细胞计数和总蛋白升高。AT2细胞显示病毒感染和BIP/GRP78表达增加的证据，与未折叠蛋白反应（UPR）的激活一致。AT2UPR包括增加的IRE1α信号传导和PERK信号的双相反应，伴随着AT2和BALF表面活性剂蛋白的显着减少（SP-B，SP-C)含量，表面活性剂表面张力增加，和重新编程的上皮细胞群的出现(Krt8+，Cldn4+）。通过用IRE1α抑制剂OPK711治疗，可以减轻稳态AT2内表型的丧失。作为概念证明，感染小鼠适应的SARS-CoV-2的C57BL6小鼠表现出相似的肺损伤和表面活性剂稳态破坏的证据。我们得出结论，β-冠状病毒感染引起的肺损伤是由激活多个AT2UPR通路的异常宿主反应引起的，改变表面活性剂代谢/功能，改变AT2内表型提供了SARS-CoV-2感染之间的机械联系，AT2细胞生物学，急性呼吸衰竭.
