Interplay of the Gastric Pathogen Helicobacter pylori with Toll-Like Receptors

Figure 1

H. pylori mediate crosstalk with Toll-like receptors (TLRs) to manipulate signaling in innate immunity. TLRs constitute a group of cell surface and subcellular transmembrane receptors in antigen-presenting cells (APCs) and epithelial cells. H. pylori can interact with at least five TLR members (TLR2, TLR4, TLR5, TLR8, and TLR9) in various ways as indicated. TLRs are composed of a leucine-rich repeat-containing ectodomain, a transmembrane region and an intracellular tail with the TIR domain. H. pylori encodes various factors that have evolved either to target or to evade detection by the TLRs. H. pylori LPS, phosphorylated lipid A of LPS, HSP-60, NapA, DNA, and RNA are reported in various studies to be recognized by specific TLRs as shown. However, nonphosphorylated lipid A and flagellin evade the recognition by TLR4 and TLR5, respectively. The TIR domain in TLRs has a crucial role in adapter protein recruitment and the activation of downstream signaling cascades. TLR activity is initiated by PAMP-induced receptor dimerization and TIR engagement with the adapter proteins MyD88 or TRIF as indicated. Binding between a given TLR and MyD88 results in the recruitment of members from the IRAK kinase family. IRAK members are sequentially phosphorylated and dissociated from MyD88. This results in the activation of TRAF6, which in turn stimulates signaling through MAP kinases and IKK complex leading to the activation of transcription factors NF-κB and AP-1 and the production of pro- and anti-inflammatory mediators. The adapter protein TRIF participates in the MyD88-independent TLR4 pathway as well as in the TLR3 signaling cascade. TRAF3 is recruited for the TRIF-mediated pathway mediating the production of type-I interferons and in some cases anti-inflammatory cytokine IL-10 [23, 24]. Endosomal TLR-mediated signaling leads to the induction of type-I interferons by the engagement of the transcription factor IRF as indicated. Question marks indicate activities/pathways which are not fully clear and require further investigation. For more details, see text.