Deficiency in Platelet 12-Lipoxygenase Exacerbates Inflammation and Disease Severity During SARS-CoV-2 Infection_data.xlsx

Platelets, known for maintaining blood balance, also participates in antimicrobial defense. Upon 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(S)-HETE) and 12(S)-hydroxyeicosatetraenoic acid (12(S)-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 NLRP1 inflammasome-related gene expression were observed. Mass spectrometry lipidomic analysis in 12-LOX deficient<i> </i>infected mice revealed significant changes in bioactive lipid content, including reduced levels of 12(S)-HETrE that inversely correlated with disease severity. Lastly, platelet 12-LOX deficiency was associated with increased morbidity and lower survival rates relative to 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.