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.

中文翻译：

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血小板 12-脂氧合酶缺乏会加剧 SARS-CoV-2 感染期间的炎症和疾病严重程度


血小板以维持血液平衡而闻名，也参与抗菌防御。严重急性呼吸系统综合症冠状病毒 2 （SARS-CoV-2） 感染后，血小板过度活跃，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），以及由环氧合酶-1 产生的前列腺素和血栓素。虽然前列腺素 E2 和血栓素 B2 以前与严重 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。使用血小板 12-LOX 缺乏的小鼠，我们报告说，相对于野生型小鼠，SARS-CoV-2 感染导致更高的肺部炎症，其特征是组织病理学组织分析、白细胞浸润增加和细胞因子产生。此外，观察到明显的血小板和肺转录组变化，包括 NOD 样受体 （NLR） 家族含 pyrin 结构域 1 （NLRP1） 炎性小体相关基因表达的改变。12-LOX 缺陷感染小鼠的质谱脂质组学分析揭示了生物活性脂质含量的显着变化，包括与疾病严重程度呈负相关的 12-HETrE 水平降低。最后，相对于野生型 （WT） 小鼠，血小板 12-LOX 缺乏与发病率增加和存活率降低相关。总体而言，本研究强调了 SARS-CoV-2 感染期间 12-LOX 相关脂质代谢与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的反应中的关键作用。