BIK polymorphism and proteasome regulation unveil host risk factor for severe influenza
Abstract
Influenza A viruses (IAVs) pose a significant public health threat, with host factors playing a crucial role in disease severity. We investigated the role of Bcl-2-interacting killer (BIK) in IAV infection using cellular and mouse models, and influenza-infected human cohort. In airway epithelial cells (AECs), BIK deficiency impaired viral replication, while BIK restoration enhanced it. Conversely, airway-specific BIK overexpression in mice increased viral load, inflammation, and mortality, whereas BIK suppression conferred protection. Critically, a genetic variation (rs738276) in the BIK gene, influencing BIK expression, correlates with altered viral replication in air–liquid interface differentiated primary normal human bronchial epithelial cells and influenza severity in humans. Mechanistically, we demonstrate that IAV nucleoprotein (NP) suppresses β5, a subunit of the proteasome, leading to increased BIK levels and enhanced viral replication. Conversely, β5 treatment dampened BIK levels and protected mice from IAV-induced morbidity and mortality. Furthermore, BIK interacts with NP, disrupting the Bcl-2/NP interaction and promoting viral replication. Our findings uncover an IAV–BIK–β5 axis that governs viral replication, suggesting that targeting BIK or β5 may offer therapeutic strategies against influenza.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Sourabh Soni
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center
Soner Yildiz
Department of Microbiology, Icahn School of Medicine at Mount Sinai
Emma Kaitlynn Allen
Department of Immunology, St. Jude Children’s Research Hospital
Hans Petersen
Chronic Obstructive Pulmonary Disease Program, Lovelace Respiratory Research Institute
Mark Peeples
Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital
Sara El Zahed
Department of Microbiology, Icahn School of Medicine at Mount Sinai
Lorena Rosas
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center
Vandana Anang
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center
Laura Antonescu
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center
Richard Seonghun Nho
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center
Ana Lucia Mora
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center
Jeffrey Craig Horowitz
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center
Mauricio Rojas
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center
Rafael Andrés Medina
Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine Emory Vaccine Center, Emory University School of Medicine
Paul Glyndwr Thomas
Department of Immunology, St. Jude Children’s Research Hospital
Adolfo García-Sastre
Yohannes Tesfaigzi
Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School
Yohannes Afework Mebratu
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center