Dos S P Andrade Ana Claudia, Lacasse Emile, Dubuc Isabelle, Gudimard Leslie, Gravel Annie, Puhm Florian, Campolina-Silva Gabriel, Queiroz-Junior Celso, Allaeys Isabelle, Prunier Julien, Azeggouar Wallen Oumaima, Dumais Élizabeth, Belleannée Clémence, Droit Arnaud, Flamand Nicolas, Boilard Éric, Flamand Louis
Division of Infectious and Immune Diseases, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec City, QC G1V 4G2, Canada.
Division of Reproduction, mother and youth health, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec City, QC G1V 4G2, Canada.
Proc Natl Acad Sci U S A. 2025 Mar 25;122(12):e2420441122. doi: 10.1073/pnas.2420441122. Epub 2025 Mar 18.
Platelets, known for maintaining blood balance, also participate in antimicrobial defense. Upon severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, platelets become hyperactivated, releasing molecules such as cytokines, granule contents, and bioactive lipids. The key effector biolipids produced by platelets include 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-hydroxyeicosatrienoic acid (12-HETrE), produced by 12-lipoxygenase (12-LOX), and prostaglandins and thromboxane, produced by cyclooxygenase-1. While prostaglandin E2 and thromboxane B2 were previously associated with lung inflammation in severe COVID-19, the role of platelet 12-LOX in SARS-CoV-2 infection remains unclear. Using mice deficient for platelets' 12-LOX, we report that SARS-CoV-2 infection resulted in higher lung inflammation characterized by histopathological tissue analysis, increased leukocyte infiltrates, and cytokine production relative to wild-type mice. In addition, distinct platelet and lung transcriptomic changes, including alterations in NOD-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) inflammasome-related gene expression, were observed. Mass spectrometry lipidomic analysis in 12-LOX-deficient-infected mice revealed significant changes in bioactive lipid content, including reduced levels of 12-HETrE that inversely correlated with disease severity. Finally, platelet 12-LOX deficiency was associated with increased morbidity and lower survival rates relative to wild type (WT) mice. Overall, this study highlights the complex interplay between 12-LOX-related lipid metabolism and inflammatory responses during SARS-CoV-2 infection. The findings provide valuable insights into potential therapeutic targets aimed at mitigating severe outcomes, emphasizing the pivotal role of platelet enzymes in the host response to viral infections.
血小板以维持血液平衡而闻名，它也参与抗菌防御。在感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）后，血小板会过度活化，释放细胞因子、颗粒内容物和生物活性脂质等分子。血小板产生的关键效应生物脂质包括由12-脂氧合酶（12-LOX）产生的12-羟基二十碳四烯酸（12-HETE）和12-羟基二十碳三烯酸（12-HETrE），以及由环氧化酶-1产生的前列腺素和血栓素。虽然前列腺素E2和血栓素B2此前被认为与重症COVID-19的肺部炎症有关，但血小板12-LOX在SARS-CoV-2感染中的作用仍不清楚。我们使用缺乏血小板12-LOX的小鼠进行研究，发现与野生型小鼠相比，SARS-CoV-2感染导致更高程度的肺部炎症，其特征为组织病理学分析显示的炎症、白细胞浸润增加和细胞因子产生增多。此外，还观察到血小板和肺部明显的转录组变化，包括含NOD样受体（NLR）家族pyrin结构域的1（NLRP1）炎性小体相关基因表达的改变。对12-LOX缺陷感染小鼠的质谱脂质组分析显示生物活性脂质含量有显著变化，包括12-HETrE水平降低，且其与疾病严重程度呈负相关。最后，与野生型（WT）小鼠相比，血小板12-LOX缺陷与发病率增加和生存率降低有关。总体而言，这项研究突出了12-LOX相关脂质代谢与SARS-CoV-2感染期间炎症反应之间的复杂相互作用。这些发现为旨在减轻严重后果的潜在治疗靶点提供了有价值的见解，强调了血小板酶在宿主对病毒感染反应中的关键作用。
