TLR4—Spike Interaction Mediates Metabolic Reprogramming in Human B Cells 2256897

Abstract

Abstract Introduction Viral infections intricately modulate B cell immunity, yet the precise underlying mechanisms remain elusive. Methods We analysed B cells from COVID-19 patients, SARS-CoV-2 Spike protein treated human primary naive B cells and mice using flow Cytometry, immunohistochemistry staining and immunoprecipitation. Results This study identifies Toll-like receptor 4 (TLR4) on human B cells as a critical metabolic sensor that detects SARS-CoV-2 spike glycoprotein and triggers mitochondrial dysfunction characterized by reduced oxidative phosphorylation, structural alteration, and elevated reactive oxygen species, leading to bioenergetic deficits. Mechanistically, TLR4 activation enhances calcium signaling via upregulation of calcium transporters independently of B cell receptor (BCR) engagement, resulting in calcium overload that disrupts mitochondrial energy production. This cascade activates AMP-activated protein kinase (AMPK), suppresses mTORC1 signaling, and downregulates key transcription factors including c-Myc, thereby impairing IgG class switching and germinal center responses. Notably, TLR4-driven mitochondrial and metabolic dysfunctioncan be reversed by TLR4 blockade. Conclusion These findings underscore TLR4’s pivotal role in orchestrating calcium mobilization and metabolic regulation in B cells, unveiling a novel mechanism by which SARS-CoV-2 subverts innate immune sensing to evade protective immunity, offering new insights for vaccine design and therapeutic interventions. Funding Source C7156-20G; 17122915; 17114114; 24231222, COVID1903010 and COVID190123; EKPG22-01 Topic Categories Viral Immunology (VIR)