Extracellular and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori.
OBJECTIVE
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.
Rad
Roland
R
II Medical Department, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
Ballhorn
Wibke
W
Voland
Petra
P
Eisenächer
Katharina
K
Mages
Jörg
J
Rad
Lena
L
Ferstl
Ruth
R
Lang
Roland
R
Wagner
Hermann
H
Schmid
Roland M
RM
Bauer
Stefan
S
Prinz
Christian
C
Kirschning
Carsten J
CJ
Krug
Anne
A
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004269:DNA, Bacterial / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000175:diagnosis; D016480:Helicobacter pylori / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D012329:RNA, Bacterial / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051193:Toll-Like Receptors / Q000172:deficiency
D004269:DNA, Bacterial; D012329:RNA, Bacterial; D051192:Receptors, Pattern Recognition; D051193:Toll-Like Receptors