Research ArticleSepsis

Targeting the TLR Co-Receptor CD14 with TLR2-Derived Peptides Modulates Immune Responses to Pathogens

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Science Translational Medicine  15 May 2013:
Vol. 5, Issue 185, pp. 185ra64
DOI: 10.1126/scitranslmed.3005544

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Influencing Immunity

Toll-like receptors (TLRs) are a type of pattern recognition receptor; they respond to conserved motifs on pathogens or produced during cellular stress and affect the downstream immune response. However, TLRs do not stand alone: One co-receptor that contributes to TLR activation is CD14. Now, Raby et al. show that targeting CD14 can modulate TLR-mediated immune responses to pathogens.

TLRs are attractive therapeutic targets because of their contributions to inflammation. The authors hypothesized that one way to target TLR activity was through CD14. They used peptide screening and mutagenesis to identify regions in TLR2 that could be involved in the TLR2-CD14 interaction. Peptides derived from these putative interacting regions enhanced the proinflammatory response of TLR2 and TLR4 to bacterial pathogens both in vitro and in vivo in a mouse model of peritonitis. Raby et al. then further identified the mechanism of this enhancement—their peptides accelerated microbial ligand transfer from CD14 to TLR2, resulting in prolonged activation. What’s more, these CD14-targeting peptides could overcome sepsis-induced immunosuppression in patient cells ex vivo. Thus, targeting CD14 may provide a therapeutic strategy for targeting TLRs.

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