Soluble Toll-Like Receptor 4 Impairs the Interaction of Shiga Toxin 2a with Human Serum Amyloid P Component

Toxins
Maurizio BrigottiXiaohua He

Abstract

Shiga toxin 2a (Stx2a) is the main virulence factor produced by pathogenic Escherichia coli strains (Stx-producing E. coli, STEC) responsible for hemorrhagic colitis and the life-threatening sequela hemolytic uremic syndrome in children. The toxin released in the intestine by STEC targets the globotriaosylceramide receptor (Gb3Cer) present on the endothelial cells of the brain and the kidney after a transient blood phase during which Stx2a interacts with blood components, such as neutrophils, which, conversely, recognize Stx through Toll-like receptor 4 (TLR4). Among non-cellular blood constituents, human amyloid P component (HuSAP) is considered a negative modulating factor that specifically binds Stx2a and impairs its toxic action. Here, we show that the soluble extracellular domain of TLR4 inhibits the binding of Stx2a to neutrophils, assessed by indirect flow cytometric analysis. Moreover, by using human sensitive Gb3Cer-expressing cells (Raji cells) we found that the complex Stx2a/soluble TLR4 escaped from capture by HuSAP allowing the toxin to target and damage human cells, as assayed by measuring translation inhibition, the typical Stx-induced functional impairment. Thus, soluble TLR4 stood out as a positive modulating f...Continue Reading

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Citations

Jan 24, 2020·Frontiers in Cellular and Infection Microbiology·Clara BerdascoJorge Goldstein
Jan 21, 2021·International Journal of Molecular Sciences·Cristina Vázquez-CarballoJuan Antonio Moreno
Mar 3, 2021·The American Journal of Pathology·Elisa VarroneMaurizio Brigotti

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Methods Mentioned

BETA
ELISA
flow cytometry

Software Mentioned

GraphPad Prism
GraphPad

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