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Published on: July 26, 2017
Targeting the TLR co-receptor CD14 with TLR2-derived peptides modulates immune responses to pathogens
Anne-Catherine Raby1, Benjamin Holst, Emmanuel Le Bouder
1Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Abstract:
Dysregulation of Toll-like receptor (TLR) responses to pathogens can lead to pathological inflammation or to immune hyporesponsiveness and susceptibility to infections, and may affect adaptive immune responses. TLRs are therefore attractive therapeutic targets. We assessed the potential of the TLR co-receptor CD14 as a target for therapeutics by investigating the magnitude of its influence on TLR responses. We studied the interaction of CD14 with TLR2 by conducting peptide screening and site-directed mutagenesis analysis and found TLR2 leucine-rich repeats 5, 9, 15, and 20 involved in interaction with CD14. Peptides representing these regions interacted with CD14 and enhanced TLR2- and TLR4-mediated proinflammatory responses to bacterial pathogens in vitro. Notably, the peptides' immune boosting capacity helped to rescue proinflammatory responses of immunosuppressed sepsis patients ex vivo. In vivo, peptide treatment increased phagocyte recruitment and accelerated bacterial clearance in murine models of Gram-negative and Gram-positive bacterial peritonitis. Up-modulating CD14's co-receptor activity with TLR2-derived peptides also enhanced antigen-induced dendritic cell (DC) maturation and interleukin-2 production and, most notably, differentially affected DC cytokine profile upon antigen stimulation, promoting a T helper 1-skewed adaptive immune response. Biochemical, cell imaging, and molecular docking studies showed that peptide binding to CD14 accelerates microbial ligand transfer from CD14 to TLR2, resulting in increased and sustained ligand occupancy of TLR2 and receptor clustering for signaling. These findings reveal the influence that CD14 exerts on TLR activities and describe a potential therapeutic strategy to amplify responses to different pathogens mediated by different TLRs by targeting the common TLR co-receptor, CD14.
Insights
Targeting the Toll-like receptor (TLR) co-receptor CD14 with peptides enhances immune responses against bacterial pathogens. This approach boosts inflammation, aids bacterial clearance, and promotes adaptive immunity, offering a potential therapeutic strategy for infections.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Toll-like receptor (TLR) dysregulation impacts inflammation and infection susceptibility.
- TLRs are critical for innate immunity and adaptive immune responses.
- CD14 acts as a co-receptor for TLRs, influencing their signaling pathways.
Purpose of the Study:
- To investigate CD14 as a therapeutic target for modulating TLR responses.
- To explore the interaction between CD14 and TLR2 using peptide screening.
- To evaluate the therapeutic potential of CD14-targeting peptides in infectious disease models.
Main Methods:
- Peptide screening and site-directed mutagenesis to identify CD14 interaction sites on TLR2.
- In vitro assays using bacterial pathogens to assess TLR2 and TLR4-mediated responses.
- Ex vivo studies with sepsis patient samples to evaluate peptide efficacy.
- In vivo studies in murine models of bacterial peritonitis.
- Analysis of dendritic cell maturation, cytokine production, and T helper cell responses.
- Biochemical, cell imaging, and molecular docking studies to elucidate the mechanism of action.
Main Results:
- Peptides derived from TLR2 LRR regions enhanced TLR2 and TLR4-mediated pro-inflammatory responses to bacterial pathogens in vitro.
- Peptide treatment rescued pro-inflammatory responses in immunosuppressed sepsis patients ex vivo.
- In vivo, peptides increased phagocyte recruitment and accelerated bacterial clearance in murine models.
- Peptides enhanced antigen-induced dendritic cell maturation and IL-2 production.
- Peptides promoted a T helper 1-skewed adaptive immune response.
- Mechanism involves accelerated microbial ligand transfer from CD14 to TLR2, enhancing receptor signaling.
Conclusions:
- CD14 is a viable therapeutic target for amplifying immune responses against pathogens.
- TLR2-derived peptides targeting CD14 demonstrate broad therapeutic potential for bacterial infections.
- This strategy enhances both innate and adaptive immunity, offering a novel approach to infectious disease treatment.
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