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      Gram-positive and gram-negative bacterial toxins in sepsis : A brief review

      review-article
      *
      Virulence
      Landes Bioscience
      LPS, TLR4, TNFα, cytokine storm, sepsis, superantigens

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          Abstract

          Bacterial sepsis is a major cause of fatality worldwide. Sepsis is a multi-step process that involves an uncontrolled inflammatory response by the host cells that may result in multi organ failure and death. Both gram-negative and gram-positive bacteria play a major role in causing sepsis. These bacteria produce a range of virulence factors that enable them to escape the immune defenses and disseminate to remote organs, and toxins that interact with host cells via specific receptors on the cell surface and trigger a dysregulated immune response. Over the past decade, our understanding of toxins has markedly improved, allowing for new therapeutic strategies to be developed. This review summarizes some of these toxins and their role in sepsis.

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          Most cited references104

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          MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4

          Toll-like receptor 4 (TLR4) is a mammalian homologue of Drosophila Toll, a leucine-rich repeat molecule that can trigger innate responses against pathogens. The TLR4 gene has recently been shown to be mutated in C3H/HeJ and C57BL/10ScCr mice, both of which are low responders to lipopolysaccharide (LPS). TLR4 may be a long-sought receptor for LPS. However, transfection of TLR4 does not confer LPS responsiveness on a recipient cell line, suggesting a requirement for an additional molecule. Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. MD-2 is thus a link between TLR4 and LPS signaling. Identification of this new receptor complex has potential implications for understanding host defense, as well as pathophysiologic, mechanisms.
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            Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.

            TLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria. Eritoran is an analog of LPS that antagonizes its activity by binding to the TLR4-MD-2 complex. We determined the structure of the full-length ectodomain of the mouse TLR4 and MD-2 complex. We also produced a series of hybrids of human TLR4 and hagfish VLR and determined their structures with and without bound MD-2 and Eritoran. TLR4 is an atypical member of the LRR family and is composed of N-terminal, central, and C-terminal domains. The beta sheet of the central domain shows unusually small radii and large twist angles. MD-2 binds to the concave surface of the N-terminal and central domains. The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4, we propose a model of TLR4-MD-2 dimerization induced by LPS.
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              CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein.

              Leukocytes respond to lipopolysaccharide (LPS) at nanogram per milliliter concentrations with secretion of cytokines such as tumor necrosis factor-alpha (TNF-alpha). Excess secretion of TNF-alpha causes endotoxic shock, an often fatal complication of infection. LPS in the bloodstream rapidly binds to the serum protein, lipopolysaccharide binding protein (LBP), and cellular responses to physiological levels of LPS are dependent on LBP. CD14, a differentiation antigen of monocytes, was found to bind complexes of LPS and LBP, and blockade of CD14 with monoclonal antibodies prevented synthesis of TNF-alpha by whole blood incubated with LPS. Thus, LPS may induce responses by interacting with a soluble binding protein in serum that then binds the cell surface protein CD14.
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                Author and article information

                Journal
                Virulence
                Virulence
                VIRU
                Virulence
                Landes Bioscience
                2150-5594
                2150-5608
                01 January 2014
                05 November 2013
                05 November 2013
                : 5
                : 1
                : 213-218
                Affiliations
                Center for Vaccine Development; Department of Medicine; University of Maryland School of Medicine; Baltimore, MD USA
                Author notes
                [* ]Correspondence to: Girish Ramachandran, Email: gramacha@ 123456medicine.umaryland.edu
                Article
                2012VIRULENCE0179R 27024
                10.4161/viru.27024
                3916377
                24193365
                030543fb-bc53-4dfd-8b31-30a925f0fe78
                Copyright © 2014 Landes Bioscience

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 21 August 2013
                : 28 October 2013
                : 31 October 2013
                Categories
                Review

                Infectious disease & Microbiology
                lps,tlr4,tnfα,cytokine storm,sepsis,superantigens
                Infectious disease & Microbiology
                lps, tlr4, tnfα, cytokine storm, sepsis, superantigens

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