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Toxins 2018, 10(9), 379;

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

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy
Immunohematology and Transfusion Center, S. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy
Center for HUS Control, Prevention and Management, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milano, Italy
European Reference Laboratory for Escherichia coli, Istituto Superiore di Sanità, 00161 Rome, Italy
Western Regional Research Center, U.S. Department of Agriculture, Agricultural Research Service, 800 Buchanan Street, Albany, CA 94710, USA
Authors to whom correspondence should be addressed.
Received: 11 August 2018 / Revised: 7 September 2018 / Accepted: 14 September 2018 / Published: 18 September 2018
(This article belongs to the Section Bacterial Toxins)
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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 factor for Stx2a. In the paper, these findings have been discussed in the context of the pathogenesis of hemolytic uremic syndrome. View Full-Text
Keywords: hemolytic uremic syndrome; HuSAP; Shiga toxins; Toll-like receptor 4; decoy receptors hemolytic uremic syndrome; HuSAP; Shiga toxins; Toll-like receptor 4; decoy receptors

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Brigotti, M.; Arfilli, V.; Carnicelli, D.; Ricci, F.; Tazzari, P.L.; Ardissino, G.; Scavia, G.; Morabito, S.; He, X. Soluble Toll-Like Receptor 4 Impairs the Interaction of Shiga Toxin 2a with Human Serum Amyloid P Component. Toxins 2018, 10, 379.

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