Coagulopathies are associated with respiratory and neurological complications in COVID-19 and long COVID. In Nature, Ryu et al. show that the soluble blood protein fibrinogen and its cleavage product fibrin, the structural component of blood clots, bind to the SARS-CoV-2 spike protein to promote activation of innate immunity in the brain and lungs. Spike protein binds to fibrin (with lower affinity than to its receptor ACE2), alters clot structure to delay its degradation by fibrinolysis, and increases the release of reactive oxygen species from bone marrow-derived macrophages compared with fibrin alone. After infection with a SARS-CoV-2 Beta variant, fibrinogen-deficient Fga^−/− or Fgg^γ390–396A mice (which retain normal clotting function but lack the γ_390–396 motif for binding to the CD11b–CD18 receptor) had reduced macrophage infiltration, alveolar hemorrhage and collagen deposition compared with wild-type mice. In addition, fibrinogen deficiency reduced the expression of genes linked to inflammation, interferon signaling and innate immunity (Irf5, Cxcl10 and Il1rn) and increased the expression of cytotoxic and NK cell genes (Prf1 and Klra9). Incubation with fibrin downregulated cytokines and chemokines responses (IFNγ and granzyme B), migration, proliferation, mitochondrial function and inflammatory (MAPK) pathways in NK cells. Deletion of NK cells in Fga^−/− or Fgg^γ390–396A mice abolished the protective effect of fibrinogen depletion, whereas treatment with 5B8, a monoclonal antibody that targets the fibrin γ_377–395 peptide, before or 24 h after infection with SARS-CoV-2 variants Beta or Delta reduced macrophage activation, oxidative stress and collagen deposition, including in the brain, in wild-type mice, which suggests that the pathway can be targeted therapeutically.

Original reference: Nature https://doi.org/10.1038/s41586-024-07873-4 (2024)

凝血功能障碍与 COVID-19 和长期 COVID 的呼吸和神经系统并发症有关。在《自然》杂志上，Ryu 等人。研究表明，可溶性血液蛋白纤维蛋白原及其裂解产物纤维蛋白（血栓的结构成分）与 SARS-CoV-2 刺突蛋白结合，促进大脑和肺部先天免疫的激活。刺突蛋白与纤维蛋白结合（其亲和力低于其受体 ACE2），改变凝块结构以延缓纤维蛋白溶解引起的降解，并与单独的纤维蛋白相比，增加骨髓源性巨噬细胞释放活性氧。感染 SARS-CoV-2 Beta 变体后，纤维蛋白原缺陷型Fga ^−/−或Fgg ^γ390–396A小鼠（保留正常凝血功能，但缺乏与 CD11b–CD18 受体结合的 γ _390–396基序）的凝血功能减少与野生型小鼠相比，巨噬细胞浸润、肺泡出血和胶原沉积。此外，纤维蛋白原缺乏会减少与炎症、干扰素信号传导和先天免疫相关的基因（ Irf5 、 Cxcl10和Il1rn ）的表达，并增加细胞毒性和NK细胞基因（ Prf1和Klra9 ）的表达。与纤维蛋白一起孵育可下调 NK 细胞中的细胞因子和趋化因子反应（IFNγ 和颗粒酶 B）、迁移、增殖、线粒体功能和炎症 (MAPK) 途径。 Fga ^−/−或Fgg ^γ390-396A小鼠中 NK 细胞的缺失消除了纤维蛋白原消耗的保护作用，而在感染 SARS 之前或感染后 24 小时，用 5B8（一种靶向纤维蛋白 γ _377-395肽的单克隆抗体）进行治疗CoV-2 变体 Beta 或 Delta 减少了野生型小鼠的巨噬细胞活化、氧化应激和胶原蛋白沉积，包括大脑中的巨噬细胞活化、氧化应激和胶原蛋白沉积，这表明该途径可以作为治疗靶点。

Original reference: Nature https://doi.org/10.1038/s41586-024-07873-4 (2024)