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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
Published on: July 26, 2017
Pilus proteins from Streptococcus pyogenes stimulate innate immune responses through Toll-like receptor 2
Risa Takahashi1, Fiona J Radcliff1,2, Thomas Proft1,2
1Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.
Abstract:
The group A Streptococcus (GAS) pilus is a long, flexible, hair-like structure anchored to the cell surface that facilitates the adherence of GAS to host cells, thus playing a critical role in initiating infections. Because of its important role in GAS virulence, the pilus has become an attractive target for vaccine development. While current research mainly focuses on pilus function and its potential as a vaccine component, there is a lack of knowledge on how the host immune system recognizes and responds to this abundant surface structure. Here we show that both assembled GAS pili and individual pilus proteins induce a potent release of the proinflammatory cytokines tumor necrosis factor and interleukin-8. We further show that the surface-exposed backbone pilin and ancillary pilin 1 subunits are Toll-like receptor 2 (TLR2) agonists. Using reporter cell lines coexpressing human TLR2 in combination with either TLR1 or TLR6, we determined that activation was mediated by the TLR2/TLR6 heterodimer. Finally, we used solid-phase and flow cytometry binding assays to illustrate a direct interaction between the pilus subunits and TLR2. These results provide further support for the suitability of the pilus as a vaccine component and opens potential avenues for using GAS pili as an adjuvant or immune-modulation agent.
Insights
Group A Streptococcus pili activate the immune system by triggering pro-inflammatory cytokine release. These pili and their proteins act as Toll-like receptor 2 (TLR2) agonists, specifically via the TLR2/TLR6 heterodimer.
Area of Science:
- Microbiology
- Immunology
- Structural Biology
Background:
- Group A Streptococcus (GAS) pili are crucial for host cell adherence and infection initiation.
- GAS pili are a key target for vaccine development due to their role in virulence.
- Limited understanding exists on how the immune system recognizes GAS pili.
Purpose of the Study:
- To investigate the immune recognition of GAS pili.
- To identify the specific immune receptors and pathways involved in GAS pilus recognition.
- To explore the potential of GAS pili in vaccine and immunotherapy strategies.
Main Methods:
- Stimulation of immune cells with GAS pili and pilus proteins.
- Measurement of pro-inflammatory cytokine release (TNF, IL-8).
- Use of reporter cell lines to identify Toll-like receptor (TLR) involvement.
- Solid-phase and flow cytometry assays to confirm direct interactions.
Main Results:
- Both assembled GAS pili and individual pilus proteins induced significant release of TNF and IL-8.
- Surface-exposed pilin and ancillary pilin 1 subunits function as TLR2 agonists.
- Immune activation was mediated by the TLR2/TLR6 heterodimer.
- Direct binding interactions were confirmed between pilus subunits and TLR2.
Conclusions:
- GAS pili and their components are potent immune stimulants.
- The TLR2/TLR6 pathway is critical for GAS pilus recognition.
- GAS pili show promise as vaccine components and as agents for immune modulation or as adjuvants.
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