Extracellular and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori
Roland Rad1, Wibke Ballhorn, Petra Voland
1II Medical Department, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
Background & Aims:
Helicobacter pylori infects half of the world's population, thereby causing significant human morbidity and mortality. The mechanisms by which professional antigen-presenting cells recognize the microbe are poorly understood.
Methods:
Using dendritic cells (DCs) from TRIF, MyD88, TLR 2/4/7/9(-/-), and multiple double/triple/quadruple mutant mice, we characterized receptors and pathways mediating innate immune recognition of H pylori.
Results:
We identified a MyD88-dependent component of the DC activation program, which was induced by surface TLRs, with TLR2 and to a minor extent also TLR4 being the exclusive surface receptors recognizing H pylori. A second MyD88-dependent component could be blocked in TLR2/4(-/-) DCs by inhibitors of endosomal acidification and depended on intracellular TLRs. We identified TLR9-mediated recognition of H pylori DNA as a principal H pylori-induced intracellular TLR pathway and further showed that H pylori RNA induces proinflammatory cytokines in a TLR-dependent manner. Microarray analysis showed complementary, redundant, and synergistic interactions between TLRs and additionally revealed gene expression patterns specific for individual TLRs, including a TLR2-dependent anti-inflammatory signature. A third component of the DC activation program was primarily composed of type I interferon-stimulated genes. This response was MyD88 and TRIF independent but was inducible by RIG-I-dependent recognition of H pylori RNA.
Conclusions:
These results provide novel comprehensive insights into the mechanisms of H pylori recognition by DCs. Understanding these processes provides a basis for the rational design of new vaccination strategies.
Insights
This study reveals how dendritic cells recognize Helicobacter pylori through various Toll-like receptors (TLRs), including surface TLR2/4 and intracellular TLR9, and RIG-I, informing new vaccine strategies.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Helicobacter pylori infection affects a significant portion of the global population, leading to substantial illness and death.
- The precise mechanisms by which antigen-presenting cells, such as dendritic cells (DCs), detect H. pylori are not well understood.
Purpose of the Study:
- To elucidate the specific receptors and signaling pathways involved in the innate immune recognition of H. pylori by dendritic cells.
- To understand the complex interplay between different Toll-like receptors (TLRs) in H. pylori detection.
Main Methods:
- Utilized dendritic cells from mutant mice lacking TRIF, MyD88, TLR 2/4/7/9, and various combinations thereof.
- Employed inhibitors of endosomal acidification to investigate intracellular TLR involvement.
- Performed microarray analysis to assess gene expression patterns in response to H. pylori.
Main Results:
- Identified a MyD88-dependent pathway involving surface TLR2 and TLR4 for H. pylori recognition.
- Discovered intracellular TLR9-mediated detection of H. pylori DNA and TLR-dependent induction of cytokines by H. pylori RNA.
- Revealed a MyD88/TRIF-independent, RIG-I-dependent pathway for H. pylori RNA recognition, leading to type I interferon responses.
Conclusions:
- Provided comprehensive insights into the multifaceted mechanisms of H. pylori recognition by dendritic cells.
- Established the roles of various TLRs and RIG-I in orchestrating innate immune responses to H. pylori.
- These findings lay the groundwork for developing improved H. pylori vaccination strategies.
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