COVID-19 is caused by SARS-CoV-2 infection and characterized by diverse clinical symptoms. Type I interferon (IFN-I) production is impaired and severe cases lead to ARDS and widespread coagulopathy. We propose that COVID-19 pathophysiology is initiated by SARS-CoV-2 gene products, the NSP1 and ORF6 proteins, leading to a catastrophic cascade of failures. These viral components induce signal transducer and activator of transcription 1 (STAT1) dysfunction and compensatory hyperactivation of STAT3. In SARS-CoV-2-infected cells, a positive feedback loop established between STAT3 and plasminogen activator inhibitor-1 (PAI-1) may lead to an escalating cycle of activation in common with the interdependent signaling networks affected in COVID-19. Specifically, PAI-1 upregulation leads to coagulopathy characterized by intravascular thrombi. Overproduced PAI-1 binds to TLR4 on macrophages, inducing the secretion of proinflammatory cytokines and chemokines. The recruitment and subsequent activation of innate immune cells within an infected lung drives the destruction of lung architecture, which leads to the infection of regional endothelial cells and produces a hypoxic environment that further stimulates PAI-1 production. Acute lung injury also activates EGFR and leads to the phosphorylation of STAT3. COVID-19 patients’ autopsies frequently exhibit diffuse alveolar damage (DAD) and increased hyaluronan (HA) production which also leads to higher levels of PAI-1. COVID-19 risk factors are consistent with this scenario, as PAI-1 levels are increased in hypertension, obesity, diabetes, cardiovascular diseases, and old age. We discuss the possibility of using various approved drugs, or drugs currently in clinical development, to treat COVID-19. This perspective suggests to enhance STAT1 activity and/or inhibit STAT3 functions for COVID-19 treatment. This might derail the escalating STAT3/PAI-1 cycle central to COVID-19.

COVID-19 由 SARS-CoV-2 感染引起，临床症状多样。I 型干扰素 (IFN-I) 的产生受损，严重病例会导致 ARDS 和广泛的凝血病。我们提出 COVID-19 的病理生理学是由 SARS-CoV-2 基因产物、NSP1 和 ORF6 蛋白引发的，导致灾难性的级联故障。这些病毒成分诱导信号转导和转录激活因子 1 (STAT1) 功能障碍和 STAT3 的代偿性过度激活。在 SARS-CoV-2 感染的细胞中，在 STAT3 和纤溶酶原激活物抑制剂-1 (PAI-1) 之间建立的正反馈回路可能导致与 COVID-19 中受影响的相互依赖的信号网络共同的激活循环升级。具体而言，PAI-1 上调导致以血管内血栓为特征的凝血功能障碍。过量产生的 PAI-1 与巨噬细胞上的 TLR4 结合，诱导促炎细胞因子和趋化因子的分泌。受感染肺内先天免疫细胞的募集和随后的激活会导致肺结构的破坏，从而导致局部内皮细胞感染并产生进一步刺激 PAI-1 产生的低氧环境。急性肺损伤也会激活 EGFR 并导致 STAT3 的磷酸化。COVID-19 患者的尸检经常表现出弥漫性肺泡损伤 (DAD) 和透明质酸 (HA) 生成增加，这也导致 PAI-1 水平升高。COVID-19 风险因素与这种情况一致，因为 PAI-1 水平在高血压、肥胖、糖尿病、心血管疾病和老年中增加。我们讨论使用各种批准药物的可能性，或目前处于临床开发阶段的药物，用于治疗 COVID-19。这一观点建议增强 STAT1 活性和/或抑制 STAT3 功能用于 COVID-19 治疗。这可能会破坏以 COVID-19 为中心的不断升级的 STAT3/PAI-1 循环。