Fibrin drives thromboinflammation and neuropathology in COVID-19 [Lung]

Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1,2,3,4. Despite the clinical evidence1,5,6,7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8,9,10. Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID. We performed bulk RNA-seq analysis from SARS-CoV-2 B.1.351 (beta variant) infected lung tissues isolated from wildtype (WT) C57BL6/L (n = 4) and Fga-/- (n = 5) mice three days post-infection. Uninfected lung samples from WT (n = 4) and Fga-/- (n = 3) mice were used as control.

威胁生命的血栓事件与神经系统症状在新型冠状病毒肺炎（COVID-19）患者中高发，且在出现新冠病毒（SARS-CoV-2）感染后急性后遗症的长新冠（long COVID）患者中持续存在[1,2,3,4]。尽管已有相关临床证据支撑[1,5,6,7]，但新冠相关凝血病的潜在分子机制、其在炎症与神经病理过程中的作用仍未被充分阐明，且当前治疗手段极为有限。纤维蛋白原（fibrinogen）作为血凝块的核心结构组分，在新冠患者的肺部与脑组织中大量沉积，与疾病严重程度呈显著正相关，同时也是新冠后认知功能缺损的预测性生物标志物[1,5,8,9,10]。本研究证实，纤维蛋白可与新冠病毒刺突蛋白（SARS-CoV-2 spike protein）结合，形成促炎性血凝块，进而驱动新冠患者体内的系统性血栓炎症与神经病理变化。在新冠病毒感染后，纤维蛋白通过其炎症结构域介导肺部的氧化应激与巨噬细胞活化，同时抑制自然杀伤细胞（natural killer cell）的功能。此外，纤维蛋白可在感染后促进神经炎症与神经元丢失，且能在不依赖活跃感染的情况下，诱导大脑与肺部的先天免疫活化。靶向炎症性纤维蛋白结构域的单克隆抗体，可保护小鼠免受感染后肺部的小胶质细胞活化、神经元损伤以及血栓炎症。综上，纤维蛋白可驱动新冠病毒感染中的炎症反应与神经病理变化，靶向纤维蛋白的免疫疗法有望成为急性新冠与长新冠患者的潜在治疗手段。
我们对感染新冠病毒B.1.351（Beta变异株）3天后的野生型（WT）C57BL6/L（n=4）与纤维蛋白原基因敲除（Fga-/-，n=5）小鼠的分离肺组织开展了批量RNA测序（bulk RNA-seq）分析。以未感染的野生型（n=4）与Fga-/-（n=3）小鼠肺组织作为对照样本。