Lipopolysaccharide-trap-Fc, a multifunctional agent to battle gram-negative bacteria.
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.
Gross
Philipp
P
Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. philipp.gross@klinik.uni-r.de
Brandl
Katharina
K
Dierkes
Christine
C
Schölmerich
Jürgen
J
Salzberger
Bernd
B
Glück
Thomas
T
Falk
Werner
W
D000818:Animals; D002460:Cell Line; D003165:Complement System Proteins / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D051218:Lymphocyte Antigen 96 / Q000235:genetics; D051379:Mice; D050296:Microbial Viability; D009000:Monocytes / Q000276:immunology; D009895:Opsonin Proteins; D010587:Phagocytosis; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D051197:Toll-Like Receptor 4 / Q000235:genetics
D007141:Immunoglobulin Fc Fragments; D007155:Immunologic Factors; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D009895:Opsonin Proteins; D011993:Recombinant Fusion Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D003165:Complement System Proteins