Microvesicle Involvement in Shiga Toxin-Associated Infection

Abstract

Shiga toxin is the main virulence factor of enterohemorrhagic Escherichia coli, a non-invasive pathogen that releases virulence factors in the intestine, causing hemorrhagic colitis and, in severe cases, hemolytic uremic syndrome (HUS). HUS manifests with acute renal failure, hemolytic anemia and thrombocytopenia. Shiga toxin induces endothelial cell damage leading to platelet deposition in thrombi within the microvasculature and the development of thrombotic microangiopathy, mostly affecting the kidney. Red blood cells are destroyed in the occlusive capillary lesions. This review focuses on the importance of microvesicles shed from blood cells and their participation in the prothrombotic lesion, in hemolysis and in the transfer of toxin from the circulation into the kidney. Shiga toxin binds to blood cells and may undergo endocytosis and be released within microvesicles. Microvesicles normally contribute to intracellular communication and remove unwanted components from cells. Many microvesicles are prothrombotic as they are tissue factor- and phosphatidylserine-positive. Shiga toxin induces complement-mediated hemolysis and the release of complement-coated red blood cell-derived microvesicles. Toxin was demonstrated within blood cell-derived microvesicles that transported it to renal cells, where microvesicles were taken up and released their contents. Microvesicles are thereby involved in all cardinal aspects of Shiga toxin-associated HUS, thrombosis, hemolysis and renal failure.

Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review

“…Indeed, lipid rafts contain caveolin where polymerization provides the platform on which to form early endosomes. The mobilization of microtubular units bring into play both clathrin-dependent [150,152] and clathrin-independent pathways [153,154]. Next, the Stx-Gb3 complex is addressed from early endosomes to the endoplasmic reticulum though retrograde transport, making it possible for Stx Gb3 to escape lysosomal degradation [155].…”

An Improved Method for the Sensitive Detection of Shiga Toxin 2 in Human Serum

“…Stahl et al found that Stx2 was present within blood cell-derived microvesicles taken up by renal cortical cells during Shiga toxin-associated infection leading to cell death. This was also observed in Stx2 treated mice and confirmed in in vitro studies, which showed that Stx2-containing blood cell-derived microvesicles undergo endocytosis in glomerular endothelial cells, which leads to cell death [ 20 , 21 ]. Brigotti et al reported detecting Stx2 in polymorphonuclear leukocytes circulating in the blood of children with HUS [ 22 ].…”

Various Facets of Pathogenic Lipids in Infectious Diseases: Exploring Virulent Lipid-Host Interactome and Their Druggability

“…The bacterial virulence factors can direct their way to the target organs by gaining access to the bloodstream, causing widespread target organ damage, such as renal failure or brain damage (Villysson et al 2017). One of the main mechanisms of toxin-induced systemic and targeted organ injury involves the transport of bacterial toxin through microvesicles (MV).…”

“…In acute cases of STEC-HUS infections, the MVs, mostly from platelets and monocytes bearing tissue factor, binds to annexin V through PS. The presence of tissue factor and PS on MVs contribute to the formation of microthrombi during the acute phases of infection (Villysson et al 2017).…”