Lipopolysaccharide-trap-Fc, a multifunctional agent to battle gram-negative bacteria. 2009

Philipp Gross, and Katharina Brandl, and Christine Dierkes, and Jürgen Schölmerich, and Bernd Salzberger, and Thomas Glück, and Werner Falk
Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. philipp.gross@klinik.uni-r.de

The family of Toll-like receptors (TLRs) plays a pivotal role in host defense against pathogens. However, overstimulation of these receptors may lead to uncontrolled general inflammation and eventually to systemic organ dysfunction or failure. With the intent to control overwhelming inflammation during gram-negative bacterial sepsis, we constructed soluble fusion proteins of the lipopolysaccharide (LPS)-receptor complex to modulate TLR signaling in multiple ways. The extracellular domain of mouse TLR4 and mouse myeloid differentiation factor 2 (MD-2) fusions (LPS-Trap) were linked to human immunoglobulin G Fc domains (LPS-Trap-Fc). In addition to the ability to bind LPS or gram-negative bacteria and to inhibit interleukin-6 secretion of monocytic cells after LPS treatment, LPS-Trap-Fc was able to opsonize fluorescent Escherichia coli particles. This led to enhancement of phagocytosis by monocytic cells which was strictly dependent on the presence of the Fc region. Moreover, only LPS-Trap-Fc- and not LPS-Trap-coated bacteria were sensitized to complement killing. Therefore, LPS-Trap-Fc not only neutralizes LPS but also, after binding to bacteria, enhances phagocytosis and complement-mediated killing and could thus act as a multifunctional agent to fight gram-negative bacteria in vivo.

UI MeSH Term Description Entries
D007141 Immunoglobulin Fc Fragments Crystallizable fragments composed of the carboxy-terminal halves of both IMMUNOGLOBULIN HEAVY CHAINS linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (COMPLEMENT fixation, binding to the cell membrane via FC RECEPTORS, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme PAPAIN. Fc Fragment,Fc Fragments,Fc Immunoglobulin,Fc Immunoglobulins,Ig Fc Fragments,Immunoglobulin Fc Fragment,Immunoglobulins, Fc,Immunoglobulins, Fc Fragment,Fc Fragment Immunoglobulins,Fc Fragment, Immunoglobulin,Fc Fragments, Ig,Fc Fragments, Immunoglobulin,Fragment Immunoglobulins, Fc,Fragment, Fc,Fragments, Ig Fc,Immunoglobulin, Fc
D007155 Immunologic Factors Biologically active substances whose activities affect or play a role in the functioning of the immune system. Biological Response Modifier,Biomodulator,Immune Factor,Immunological Factor,Immunomodulator,Immunomodulators,Biological Response Modifiers,Biomodulators,Factors, Immunologic,Immune Factors,Immunological Factors,Modifiers, Biological Response,Response Modifiers, Biological,Factor, Immune,Factor, Immunological,Factors, Immune,Factors, Immunological,Modifier, Biological Response,Response Modifier, Biological
D009000 Monocytes Large, phagocytic mononuclear leukocytes produced in the vertebrate BONE MARROW and released into the BLOOD; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. Monocyte
D009895 Opsonin Proteins Proteins that bind to particles and cells to increase susceptibility to PHAGOCYTOSIS, especially ANTIBODIES bound to EPITOPES that attach to FC RECEPTORS. COMPLEMENT C3B may also participate. Opsonin,Opsonin Protein,Opsonins,Protein, Opsonin
D010587 Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (PHAGOCYTES). Phagocytoses
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D011993 Recombinant Fusion Proteins Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes. Fusion Proteins, Recombinant,Recombinant Chimeric Protein,Recombinant Fusion Protein,Recombinant Hybrid Protein,Chimeric Proteins, Recombinant,Hybrid Proteins, Recombinant,Recombinant Chimeric Proteins,Recombinant Hybrid Proteins,Chimeric Protein, Recombinant,Fusion Protein, Recombinant,Hybrid Protein, Recombinant,Protein, Recombinant Chimeric,Protein, Recombinant Fusion,Protein, Recombinant Hybrid,Proteins, Recombinant Chimeric,Proteins, Recombinant Fusion,Proteins, Recombinant Hybrid
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D003165 Complement System Proteins Serum glycoproteins participating in the host defense mechanism of COMPLEMENT ACTIVATION that creates the COMPLEMENT MEMBRANE ATTACK COMPLEX. Included are glycoproteins in the various pathways of complement activation (CLASSICAL COMPLEMENT PATHWAY; ALTERNATIVE COMPLEMENT PATHWAY; and LECTIN COMPLEMENT PATHWAY). Complement Proteins,Complement,Complement Protein,Hemolytic Complement,Complement, Hemolytic,Protein, Complement,Proteins, Complement,Proteins, Complement System
D004926 Escherichia coli A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc. Alkalescens-Dispar Group,Bacillus coli,Bacterium coli,Bacterium coli commune,Diffusely Adherent Escherichia coli,E coli,EAggEC,Enteroaggregative Escherichia coli,Enterococcus coli,Diffusely Adherent E. coli,Enteroaggregative E. coli,Enteroinvasive E. coli,Enteroinvasive Escherichia coli

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