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Life sciences · Journal article
The Journal of Immunology · July 28, 2026
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This mechanistic study identifies TLR4 as a metabolic sensor on human B cells that responds to SARS-CoV-2 spike glycoprotein, triggering calcium overload, mitochondrial dysfunction, and suppression of antibody class switching and germinal center responses. The pathway can be reversed by TLR4 blockade in vitro, but no clinical efficacy data, quantified effect sizes, or human in vivo validation are provided.
Mechanistic ex vivo study with human primary B cells, COVID-19 patient samples, and mouse models. B cells from COVID-19 patients; primary naive human B cells; mouse B cells. Intervention: SARS-CoV-2 spike glycoprotein treatment; TLR4 blockade.
TLR4 activation by spike glycoprotein triggers mitochondrial dysfunction characterized by reduced oxidative phosphorylation, structural alteration, and elevated reactive oxygen species TLR4-driven calcium signaling occurs independently of B cell receptor engagement via upregulation of calcium transporters Calcium overload activates AMPK, suppresses mTORC1 signaling, and downregulates c-Myc, impairing IgG class switching and germinal center responses
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These findings suggest TLR4-mediated metabolic suppression may contribute to B cell dysfunction in COVID-19 and could inform vaccine design strategies to enhance rather than suppress TLR4 signaling or selectively block this pathway to prevent pathogenic responses. Validation in human in vivo studies and clinical trials is needed before therapeutic application.
Mechanistic study in primary human B cells and mice identifying TLR4–spike interaction as a metabolic checkpoint, but lacks clinical efficacy data, controlled comparisons of effect sizes, or validation in vivo; findings are pathway-descriptive rather than practice-changing.
As stated by the source record.
These findings suggest TLR4-mediated metabolic suppression may contribute to B cell dysfunction in COVID-19 and could inform vaccine design strategies to enhance rather than suppress TLR4 signaling or selectively block this pathway to prevent pathogenic responses. Validation in human in vivo studies and clinical trials is needed before therapeutic application.
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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)
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