ADP-heptose is a newly identified pathogen-associated molecular pattern of Shigella flexneri
Diego García-Weber1,2,3, Anne-Sophie Dangeard1,2,3, Johan Cornil4,5
1INSERM, U1016, Institut Cochin, Paris, France.
Abstract:
During an infection, the detection of pathogens is mediated through the interactions between pathogen-associated molecular patterns (PAMPs) and pathogen recognition receptors. β-Heptose 1,7-bisphosphate (βHBP), an intermediate of the lipopolysaccharide (LPS) biosynthesis pathway, was recently identified as a bacterial PAMP. It was reported that βHBP sensing leads to oligomerization of TIFA proteins, a mechanism controlling NF-κB activation and pro-inflammatory gene expression. Here, we compare the ability of chemically synthesized βHBP and Shigella flexneri lysate to induce TIFA oligomerization in epithelial cells. We find that, unlike bacterial lysate, βHBP fails to initiate rapid TIFA oligomerization. It only induces delayed signaling, suggesting that βHBP must be processed intracellularly to trigger inflammation. Gene deletion and complementation analysis of the LPS biosynthesis pathway revealed that ADP-heptose is the bacterial metabolite responsible for rapid TIFA oligomerization. ADP-heptose sensing occurs down to 10-10 M. During S. flexneri infection, it results in cytokine production, a process dependent on the kinase ALPK1. Altogether, our results rule out a major role of βHBP in S. flexneri infection and identify ADP-heptose as a new bacterial PAMP.
Insights
ADP-heptose, not β-heptose 1,7-bisphosphate (βHBP), triggers rapid TIFA oligomerization and inflammation during Shigella flexneri infection. ADP-heptose is identified as a novel bacterial PAMP.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Pathogen recognition involves pathogen-associated molecular patterns (PAMPs) binding to pattern recognition receptors.
- β-Heptose 1,7-bisphosphate (βHBP) was proposed as a PAMP, inducing TIFA protein oligomerization and NF-κB activation.
- TIFA oligomerization is a key pathway for initiating inflammatory responses.
Purpose of the Study:
- To investigate the role of β-heptose 1,7-bisphosphate (βHBP) in initiating TIFA oligomerization and inflammatory signaling.
- To identify the specific bacterial metabolite responsible for rapid TIFA oligomerization during Shigella flexneri infection.
- To characterize the sensing mechanism and inflammatory potential of novel PAMPs.
Main Methods:
- Chemically synthesized βHBP and Shigella flexneri lysate were used to stimulate epithelial cells.
- TIFA oligomerization was assessed in response to different bacterial components.
- Gene deletion and complementation analysis of the lipopolysaccharide (LPS) biosynthesis pathway were performed.
- Cytokine production and ALPK1-dependent signaling were measured.
Main Results:
- βHBP failed to induce rapid TIFA oligomerization, showing only delayed signaling.
- ADP-heptose, an intermediate in LPS biosynthesis, was identified as the metabolite inducing rapid TIFA oligomerization.
- ADP-heptose sensing was detected at concentrations as low as 10⁻¹⁰ M.
- ADP-heptose triggered cytokine production in an ALPK1-dependent manner during S. flexneri infection.
Conclusions:
- βHBP does not appear to play a significant role in S. flexneri-induced inflammation.
- ADP-heptose is identified as a novel bacterial PAMP responsible for rapid TIFA oligomerization and pro-inflammatory signaling.
- The findings elucidate a new mechanism of innate immune recognition involving ADP-heptose sensing.
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