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

Pachathundikandi SK, Lind J, Tegtmeyer N, El-Omar EM, Backert S - Biomed Res Int (2015)

Bottom Line: Toll-like receptors (TLRs) are crucial for pathogen recognition and downstream signaling to induce effective immunity.Activation of TLRs and resulting signal transduction events lead to the production of pro- and anti-inflammatory mediators through activation of NF-κB, MAP kinases, and IRF signaling pathways.Hence, the interplay of TLRs and bacterial factors highlight the complexity of innate immune recognition and immune evasion as well as regulated processes in the progression of associated pathologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Division of Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstraße 5, 91058 Erlangen, Germany.

ABSTRACT
Toll-like receptors (TLRs) are crucial for pathogen recognition and downstream signaling to induce effective immunity. The gastric pathogen Helicobacter pylori is a paradigm of persistent bacterial infections and chronic inflammation in humans. The chronicity of inflammation during H. pylori infection is related to the manipulation of regulatory cytokines. In general, the early detection of H. pylori by TLRs and other pattern recognition receptors (PRRs) is believed to induce a regulatory cytokine or chemokine profile that eventually blocks the resolution of inflammation. H. pylori factors such as LPS, HSP-60, NapA, DNA, and RNA are reported in various studies to be recognized by specific TLRs. However, H. pylori flagellin evades the recognition of TLR5 by possessing a conserved N-terminal motif. Activation of TLRs and resulting signal transduction events lead to the production of pro- and anti-inflammatory mediators through activation of NF-κB, MAP kinases, and IRF signaling pathways. The genetic polymorphisms of these important PRRs are also implicated in the varied outcome and disease progression. Hence, the interplay of TLRs and bacterial factors highlight the complexity of innate immune recognition and immune evasion as well as regulated processes in the progression of associated pathologies. Here we will review this important aspect of H. pylori infection.

No MeSH data available.


Related in: MedlinePlus

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.
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fig1: 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.

Mentions: TLRs constitute a group of cell surface and subcellular transmembrane proteins, which are expressed on cells of the host immune system including macrophages and dendritic cells (DCs) but are also present on the gastrointestinal epithelium and other nonimmune cells [19–21]. TLRs belong to the class of pattern recognition receptors (PRR) of the host innate immune system. These germ line encoded type I transmembrane glycosylated protein receptors are composed of an ectodomain with leucine-rich repeats (LRR), transmembrane region, and intracytoplasmic Toll/IL-1 receptor (TIR) domain [20–22]. TLRs act as sensors where they recognize microbial pathogens of bacterial, viral, fungal, and protozoan origin. A wide variety of ligands can bind to different TLRs to induce downstream signaling. The ligands are called pathogen associated molecular patterns (PAMPs) and include a broad array of microbial molecules build-up of proteins, nucleic acids, lipids, or synthetic chemicals. Upon activation by microbial factors, TLRs trigger the coordinated expression of host genes involved in specific signaling cascades for the regulation of innate and adaptive immunity, tissue repair, and regeneration processes [19, 20]. By binding of microbial ligands to a given TLR, there is activation of signaling transduction pathways involving the TIR domain and binding to cytoplasmic adaptor molecules including myeloid differentiation factor 88 (MyD88), TIR domain-containing protein (TIRAP), TIR domain-containing adaptor inducing interferon-beta (TRIF), and TIR domain-containing adaptor inducing interferon-β-related adaptor molecule (TRAM). This complex has been described to activate two main signaling pathways, the MyD88-dependent (applied by most TLRs except TLR3) and the MyD88-independent TRAM/TRIF cascade (applied by TLR3 and some signals of TLR4) [20–22]. The MyD88-dependent pathway signals through a cascade of interleukin-1 receptor associated kinase (IRAK), tumor necrosis factor receptor associated factor 6 (TRAF6), and transforming growth factor-beta-activated kinase 1 (TAK1) and activates transcription factor nuclear factor kappa B (NF-κB) and its translocation from the cytoplasm to the nucleus as well as c-jun N-terminal kinase (JNK) and p38-mediated activator protein 1 (AP-1) stimulation [19–21]. NF-κB and AP-1 can then bind to the promoter region of a variety of immune and inflammatory genes resulting in the transcription of proinflammatory and anti-inflammatory cytokines, including tumor necrosis factor- (TNF-) α and interleukin-6 (IL-6). The MyD88-independent pathway uses TRAM/TRIF adaptor proteins for initiating signaling, which leads to the cascade involving TRAF3, inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε), and TANK binding kinase 1 (TBK-1) to the production of type-1 interferons [19–21]. In addition, the TRIF pathway was reported to activate NF-κB through a cascade involving receptor interacting protein 1 (RIP1) and TAK1. In this manner, TLRs regulate the production of cytokines, opsonization, coagulation cascades, complement activation, and upregulation of costimulatory molecules on antigen presenting cells. However, exact role of TLRs in H. pylori infection is highly controversial in the literature and needs to be reviewed. The various reported interactions with TLR2, TLR4, TLR5, TLR8, and TLR9 as well as some identified bacterial interaction partners and resulting downstream targets are summarized in Table 1. An overall model for major TLR activities and proposed signaling strategies exploited by H. pylori is presented in Figure 1.


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

Pachathundikandi SK, Lind J, Tegtmeyer N, El-Omar EM, Backert S - Biomed Res Int (2015)

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.
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Related In: Results  -  Collection

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fig1: 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.
Mentions: TLRs constitute a group of cell surface and subcellular transmembrane proteins, which are expressed on cells of the host immune system including macrophages and dendritic cells (DCs) but are also present on the gastrointestinal epithelium and other nonimmune cells [19–21]. TLRs belong to the class of pattern recognition receptors (PRR) of the host innate immune system. These germ line encoded type I transmembrane glycosylated protein receptors are composed of an ectodomain with leucine-rich repeats (LRR), transmembrane region, and intracytoplasmic Toll/IL-1 receptor (TIR) domain [20–22]. TLRs act as sensors where they recognize microbial pathogens of bacterial, viral, fungal, and protozoan origin. A wide variety of ligands can bind to different TLRs to induce downstream signaling. The ligands are called pathogen associated molecular patterns (PAMPs) and include a broad array of microbial molecules build-up of proteins, nucleic acids, lipids, or synthetic chemicals. Upon activation by microbial factors, TLRs trigger the coordinated expression of host genes involved in specific signaling cascades for the regulation of innate and adaptive immunity, tissue repair, and regeneration processes [19, 20]. By binding of microbial ligands to a given TLR, there is activation of signaling transduction pathways involving the TIR domain and binding to cytoplasmic adaptor molecules including myeloid differentiation factor 88 (MyD88), TIR domain-containing protein (TIRAP), TIR domain-containing adaptor inducing interferon-beta (TRIF), and TIR domain-containing adaptor inducing interferon-β-related adaptor molecule (TRAM). This complex has been described to activate two main signaling pathways, the MyD88-dependent (applied by most TLRs except TLR3) and the MyD88-independent TRAM/TRIF cascade (applied by TLR3 and some signals of TLR4) [20–22]. The MyD88-dependent pathway signals through a cascade of interleukin-1 receptor associated kinase (IRAK), tumor necrosis factor receptor associated factor 6 (TRAF6), and transforming growth factor-beta-activated kinase 1 (TAK1) and activates transcription factor nuclear factor kappa B (NF-κB) and its translocation from the cytoplasm to the nucleus as well as c-jun N-terminal kinase (JNK) and p38-mediated activator protein 1 (AP-1) stimulation [19–21]. NF-κB and AP-1 can then bind to the promoter region of a variety of immune and inflammatory genes resulting in the transcription of proinflammatory and anti-inflammatory cytokines, including tumor necrosis factor- (TNF-) α and interleukin-6 (IL-6). The MyD88-independent pathway uses TRAM/TRIF adaptor proteins for initiating signaling, which leads to the cascade involving TRAF3, inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε), and TANK binding kinase 1 (TBK-1) to the production of type-1 interferons [19–21]. In addition, the TRIF pathway was reported to activate NF-κB through a cascade involving receptor interacting protein 1 (RIP1) and TAK1. In this manner, TLRs regulate the production of cytokines, opsonization, coagulation cascades, complement activation, and upregulation of costimulatory molecules on antigen presenting cells. However, exact role of TLRs in H. pylori infection is highly controversial in the literature and needs to be reviewed. The various reported interactions with TLR2, TLR4, TLR5, TLR8, and TLR9 as well as some identified bacterial interaction partners and resulting downstream targets are summarized in Table 1. An overall model for major TLR activities and proposed signaling strategies exploited by H. pylori is presented in Figure 1.

Bottom Line: Toll-like receptors (TLRs) are crucial for pathogen recognition and downstream signaling to induce effective immunity.Activation of TLRs and resulting signal transduction events lead to the production of pro- and anti-inflammatory mediators through activation of NF-κB, MAP kinases, and IRF signaling pathways.Hence, the interplay of TLRs and bacterial factors highlight the complexity of innate immune recognition and immune evasion as well as regulated processes in the progression of associated pathologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Division of Microbiology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstraße 5, 91058 Erlangen, Germany.

ABSTRACT
Toll-like receptors (TLRs) are crucial for pathogen recognition and downstream signaling to induce effective immunity. The gastric pathogen Helicobacter pylori is a paradigm of persistent bacterial infections and chronic inflammation in humans. The chronicity of inflammation during H. pylori infection is related to the manipulation of regulatory cytokines. In general, the early detection of H. pylori by TLRs and other pattern recognition receptors (PRRs) is believed to induce a regulatory cytokine or chemokine profile that eventually blocks the resolution of inflammation. H. pylori factors such as LPS, HSP-60, NapA, DNA, and RNA are reported in various studies to be recognized by specific TLRs. However, H. pylori flagellin evades the recognition of TLR5 by possessing a conserved N-terminal motif. Activation of TLRs and resulting signal transduction events lead to the production of pro- and anti-inflammatory mediators through activation of NF-κB, MAP kinases, and IRF signaling pathways. The genetic polymorphisms of these important PRRs are also implicated in the varied outcome and disease progression. Hence, the interplay of TLRs and bacterial factors highlight the complexity of innate immune recognition and immune evasion as well as regulated processes in the progression of associated pathologies. Here we will review this important aspect of H. pylori infection.

No MeSH data available.


Related in: MedlinePlus