Synthetic toll like receptor-4 (TLR-4) agonist peptides as a novel class of adjuvants

Arul Kumaran Shanmugam, Shilpi Rajoria, Andrea L. George, Abraham Mittelman, Robert Suriano, Raj K. Tiwari

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background: Adjuvants 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 Findings: We 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/Significance: Our 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.

Original languageEnglish (US)
Article numbere30839
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 20 2012

Fingerprint

Toll-Like Receptor 4
lipopolysaccharides
agonists
adjuvants
Lipopolysaccharides
peptides
Peptides
inflammation
synthetic peptides
Toll-Like Receptors
Cells
Inflammation
Toll-like receptor 4
septic shock
Signal transduction
Bacteriophages
Macrophages
mice
Septic Shock
Gram-Negative Bacteria

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Shanmugam, A. K., Rajoria, S., George, A. L., Mittelman, A., Suriano, R., & Tiwari, R. K. (2012). Synthetic toll like receptor-4 (TLR-4) agonist peptides as a novel class of adjuvants. PLoS One, 7(2), [e30839]. https://doi.org/10.1371/journal.pone.0030839

Synthetic toll like receptor-4 (TLR-4) agonist peptides as a novel class of adjuvants. / Shanmugam, Arul Kumaran; Rajoria, Shilpi; George, Andrea L.; Mittelman, Abraham; Suriano, Robert; Tiwari, Raj K.

In: PLoS One, Vol. 7, No. 2, e30839, 20.02.2012.

Research output: Contribution to journalArticle

Shanmugam, AK, Rajoria, S, George, AL, Mittelman, A, Suriano, R & Tiwari, RK 2012, 'Synthetic toll like receptor-4 (TLR-4) agonist peptides as a novel class of adjuvants', PLoS One, vol. 7, no. 2, e30839. https://doi.org/10.1371/journal.pone.0030839
Shanmugam AK, Rajoria S, George AL, Mittelman A, Suriano R, Tiwari RK. Synthetic toll like receptor-4 (TLR-4) agonist peptides as a novel class of adjuvants. PLoS One. 2012 Feb 20;7(2). e30839. https://doi.org/10.1371/journal.pone.0030839
Shanmugam, Arul Kumaran ; Rajoria, Shilpi ; George, Andrea L. ; Mittelman, Abraham ; Suriano, Robert ; Tiwari, Raj K. / Synthetic toll like receptor-4 (TLR-4) agonist peptides as a novel class of adjuvants. In: PLoS One. 2012 ; Vol. 7, No. 2.
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