Abstract
BackgroundAdjuvants serve as catalysts of the innate immune response by initiating a localized site of inflammation that is mitigated by the interactions between antigens and toll like receptor (TLR) proteins. Currently, the majority of vaccines are formulated with aluminum based adjuvants, which are associated with various side effects. In an effort to develop a new class of adjuvants, agonists of TLR proteins, such as bacterial products, would be natural candidates. Lipopolysaccharide (LPS), a major structural component of gram negative bacteria cell walls, induces the systemic inflammation observed in septic shock by interacting with TLR-4. The use of synthetic peptides of LPS or TLR-4 agonists, which mimic the interaction between TLR-4 and LPS, can potentially regulate cellular signal transduction pathways such that a localized inflammatory response is achieved similar to that generated by adjuvants.Methodology/Principal FindingsWe report the identification and activity of several peptides isolated using phage display combinatorial peptide technology, which functionally mimicked LPS. The activity of the LPS-TLR-4 interaction was assessed by NF-κB nuclear translocation analyses in HEK-BLUE™-4 cells, a cell culture model that expresses only TLR-4, and the murine macrophage cell line, RAW264.7. Furthermore, the LPS peptide mimics were capable of inducing inflammatory cytokine secretion from RAW264.7 cells. Lastly, ELISA analysis of serum from vaccinated BALB/c mice revealed that the LPS peptide mimics act as a functional adjuvant.Conclusions/SignificanceOur data demonstrate the identification of synthetic peptides that mimic LPS by interacting with TLR-4. This LPS mimotope-TLR-4 interaction will allow for the development and use of these peptides as a new class of adjuvants, namely TLR-4 agonists.
Highlights
Lipopolysaccharide (LPS) is the major structural component of gram negative bacteria and is composed of three distinct domains; lipid A, a core oligosaccharide chain, and an O-antigen [1,2]
Of all three LPS domains discussed, the O-antigen is of most significance as it distinguishes between various gram negative bacterial strains and most importantly, it is recognized by the immune system during infection [2,3]
Adjuvants provide a bridge between antigens and antigen presenting cells (APC) of the immune system [27]
Summary
Lipopolysaccharide (LPS) is the major structural component of gram negative bacteria and is composed of three distinct domains; lipid A, a core oligosaccharide chain, and an O-antigen [1,2]. Of all three LPS domains discussed, the O-antigen is of most significance as it distinguishes between various gram negative bacterial strains and most importantly, it is recognized by the immune system during infection [2,3]. It is this recognition and interaction between LPS and the immune system, the innate branch of the immune system, which leads to a potentially life threatening condition known as sepsis. Lipopolysaccharide (LPS), a major structural component of gram negative bacteria cell walls, induces the systemic inflammation observed in septic shock by interacting with TLR-4. The use of synthetic peptides of LPS or TLR-4 agonists, which mimic the interaction between TLR-4 and LPS, can potentially regulate cellular signal transduction pathways such that a localized inflammatory response is achieved similar to that generated by adjuvants
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