Scientific Officer The University of Hong Kong, United States
Disclosure(s):
Li Liu, PhD: No financial relationships to disclose
Introduction/Rationale: 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.
