Deficiency in platelet 12-lipoxygenase exacerbates inflammation and disease severity during SARS-CoV-2 infection
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Ana Claudia dos S. P. Andrade
Division of Infectious and Immune Diseases, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Emile Lacasse
Division of Infectious and Immune Diseases, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Isabelle Dubuc
Division of Infectious and Immune Diseases, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Leslie Gudimard
Division of Infectious and Immune Diseases, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Annie Gravel
Division of Infectious and Immune Diseases, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Florian Puhm
Division of Infectious and Immune Diseases, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Gabriel Campolina-Silva
Division of Reproduction, mother and youth health, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Celso Queiroz-Junior
Morphology Department, Universidade Federal de Minas Gerais
Isabelle Allaeys
Division of Infectious and Immune Diseases, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Julien Prunier
Division of Endocrinology and Nephrology, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Oumaima Azeggouar Wallen
Centre de recherche de l’Institut Universitaire de cardiologie et pneumologie de Québec, Division of pneumology, Faculty of medicine, Université Laval
Élizabeth Dumais
Centre de recherche de l’Institut Universitaire de cardiologie et pneumologie de Québec, Division of pneumology, Faculty of medicine, Université Laval
Clémence Belleannée
Division of Reproduction, mother and youth health, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Arnaud Droit
Nicolas Flamand
Centre de recherche de l’Institut Universitaire de cardiologie et pneumologie de Québec, Division of pneumology, Faculty of medicine, Université Laval
Éric Boilard
Division of Infectious and Immune Diseases, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval
Louis Flamand
Division of Infectious and Immune Diseases, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval