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      Verotoxin Receptor-Based Pathology and Therapies

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          Abstract

          Verotoxin, VT (aka Shiga toxin,Stx) is produced by enterohemorrhagic E. coli (EHEC) and is the key pathogenic factor in EHEC-induced hemolytic uremic syndrome (eHUS-hemolytic anemia/thrombocytopenia/glomerular infarct) which can follow gastrointestinal EHEC infection, particularly in children. This AB5 subunit toxin family bind target cell globotriaosyl ceramide (Gb 3), a glycosphingolipid (GSL) (aka CD77, pk blood group antigen) of the globoseries of neutral GSLs, initiating lipid raft-dependent plasma membrane Gb 3 clustering, membrane curvature, invagination, scission, endosomal trafficking, and retrograde traffic via the TGN to the Golgi, and ER. In the ER, A/B subunits separate and the A subunit hijacks the ER reverse translocon (dislocon-used to eliminate misfolded proteins-ER associated degradation-ERAD) for cytosolic access. This property has been used to devise toxoid-based therapy to temporarily block ERAD and rescue the mutant phenotype of several genetic protein misfolding diseases. The A subunit avoids cytosolic proteosomal degradation, to block protein synthesis via its RNA glycanase activity. In humans, Gb 3 is primarily expressed in the kidney, particularly in the glomerular endothelial cells. Here, Gb 3 is in lipid rafts (more ordered membrane domains which accumulate GSLs/cholesterol) whereas renal tubular Gb 3 is in the non-raft membrane fraction, explaining the basic pathology of eHUS (glomerular endothelial infarct). Females are more susceptible and this correlates with higher renal Gb 3 expression. HUS can be associated with encephalopathy, more commonly following verotoxin 2 exposure. Gb 3 is expressed in the microvasculature of the brain. All members of the VT family bind Gb 3, but with varying affinity. VT2e (pig edema toxin) binds Gb 4 preferentially. Verotoxin-specific therapeutics based on chemical analogs of Gb 3, though effective in vitro, have failed in vivo. While some analogs are effective in animal models, there are no good rodent models of eHUS since Gb 3 is not expressed in rodent glomeruli. However, the mouse mimics the neurological symptoms more closely and provides an excellent tool to assess therapeutics. In addition to direct cytotoxicity, other factors including VT–induced cytokine release and aberrant complement cascade, are now appreciated as important in eHUS. Based on atypical HUS therapy, treatment of eHUS patients with anticomplement antibodies has proven effective in some cases. A recent switch using stem cells to try to reverse, rather than prevent VT induced pathology may prove a more effective methodology.

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          To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps

          Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.
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            Shiga toxin induces tubular membrane invaginations for its uptake into cells.

            Clathrin seems to be dispensable for some endocytic processes and, in several instances, no cytosolic coat protein complexes could be detected at sites of membrane invagination. Hence, new principles must in these cases be invoked to account for the mechanical force driving membrane shape changes. Here we show that the Gb3 (glycolipid)-binding B-subunit of bacterial Shiga toxin induces narrow tubular membrane invaginations in human and mouse cells and model membranes. In cells, tubule occurrence increases on energy depletion and inhibition of dynamin or actin functions. Our data thus demonstrate that active cellular processes are needed for tubule scission rather than tubule formation. We conclude that the B-subunit induces lipid reorganization that favours negative membrane curvature, which drives the formation of inward membrane tubules. Our findings support a model in which the lateral growth of B-subunit-Gb3 microdomains is limited by the invagination process, which itself is regulated by membrane tension. The physical principles underlying this basic cargo-induced membrane uptake may also be relevant to other internalization processes, creating a rationale for conceptualizing the perplexing diversity of endocytic routes.
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              Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice.

              Shiga toxin-producing Escherichia coli (STEC) cause significant disease; treatment is supportive and antibiotic use is controversial. Ciprofloxacin but not fosfomycin causes Shiga toxin-encoding bacteriophage induction and enhanced Shiga toxin (Stx) production from E. coli O157:H7 in vitro. The potential clinical relevance of this was examined in mice colonized with E. coli O157:H7 and given either ciprofloxacin or fosfomycin. Both antibiotics caused a reduction in fecal STEC. However, animals treated with ciprofloxacin had a marked increase in free fecal Stx, associated with death in two-thirds of the mice, whereas fosfomycin did not. Experiments that used a kanamycin-marked Stx2 prophage demonstrated that ciprofloxacin, but not fosfomycin, caused enhanced intraintestinal transfer of Stx2 prophage from one E. coli to another. These observations suggest that treatment of human STEC infection with bacteriophage-inducing antibiotics, such as fluoroquinolones, may have significant adverse clinical consequences and that fluoroquinolone antibiotics may enhance the movement of virulence factors in vivo.
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                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                31 March 2020
                2020
                : 10
                : 123
                Affiliations
                Molecular Medicine, Research Institute, Hospital for Sick Children , Toronto, ON, Canada
                Author notes

                Edited by: Vernon L. Tesh, Texas A&M University, United States

                Reviewed by: Ludger Johannes, Maria Sklodowska Curie Institute of Oncology, Poland; Angela Melton-Celsa, Uniformed Services University, United States

                *Correspondence: Clifford Lingwood cling@ 123456sickkids.ca

                This article was submitted to Molecular Bacterial Pathogenesis, a section of the journal Frontiers in Cellular and Infection Microbiology

                Article
                10.3389/fcimb.2020.00123
                7136409
                d41d9da5-faeb-4c34-b924-486b758d76eb
                Copyright © 2020 Lingwood.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 November 2019
                : 05 March 2020
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 168, Pages: 10, Words: 9223
                Categories
                Cellular and Infection Microbiology
                Mini Review

                Infectious disease & Microbiology
                lipid raft,retrograde transport,endothelial cell,astrocyte,hemolytic uremic syndrome

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