Figures & data
Table 1. Targeted host cell protein receptors interacting with known ligands of H. pylori.
Figure 1. Model of Helicobacter pylori-mediated contact with host protein receptors on epithelial and immune cells to trigger bacterial binding and/or downstream signal transduction events. The interplay between gastric epithelial and various types of immune cells with bacterial pathogenicity factors modulates multiple host responses during the course of infection as indicated. (A) H. pylori expresses several adhesins, some of which can bind to a host protein receptor. One example is the AlpA and AlpB adhesins binding to the matrix protein laminin. Attached H. pylori or those swimming in the mucus can secrete virulence factors into the medium including VacA and urease. VacA is a pore-forming toxin and can bind to various host surface receptors such as the RPTP tyrosine phosphatases. Internalization of VacA into cells leads to the formation of large vacuoles and gastric damage, a hallmark of the ulceration process. VacA can also trigger p38 MAP kinase activation, nuclear responses and mitochondria-associated apoptosis. (B) The H. pylori urease complex has an important function in buffering the acidic pH in the human stomach. However, urease B can also bind directly to the CD74 [MHC-II (class II major histocompatibility complex)-associated invariant chain] receptor on host cells, possibly activating the pro-inflammatory transcription factor NFκB and IL-8 release. Another receptor, CD46, acts as a bactericidal factor as it can bind to the urease A subunit and inhibits H. pylori urease activity. (C) After adherence, H. pylori can translocate effector molecules, such as CagA and peptidoglycan, into the host cell using a type IV secretion system (T4SS)-dependent process. Peptidoglycan binds to the intracellular receptor NOD1, activating transcription factors NFκB or IRF7 to stimulate the secretion of IL-8 or interferon-γ (IFNγ), respectively. (D) Injection of CagA requires various indicated T4SS pilus components and a host protein receptor, integrin β1. Since integrins are normally basolateral receptors, it is not yet clear if injection of CagA appears at apical or basolateral surfaces. However, injected CagA can interact with a number of host cell signaling molecules to trigger several signaling cascades as shown. For example, CagA can bind to PAR-1 and E-cadherin, possibly affecting cell polarity. CagA also contributes to sustained NFκB activity, inhibition of gastric acid production and cell elongation by targeting the actin-binding protein cortactin. (E) The H. pylori T4SS can also activate a number of receptor tyrosine kinases (RTKs) including EGFR, ErbB2, ErbB3 and c-Met which play various roles as indicated. Some yet undefined inhibitory activities on EGFR activation and wound healing have been attributed to VacA. (F) H. pylori targets the glycoprotein receptor GP130 using CagA (phosphorylated by Src and Abl kinases) to activate signal transducer and activation of transcription (STAT) signaling. (G) A novel CagL→integrin αvβ5 signaling complex was characterized to trigger gastrin expression. CagL can also bind to another integrin member, αvβ3, but the resulting downstream signaling is not yet clear. (H) Targeting of tight junctions and E-cadherin-based adherens junctions by the serine protease HtrA and CagA contribute to the disruption of the epithelial barrier. These events may cause leakage of nutrients into the gastric lumen and the ability of H. pylori to cross the epithelial layer by a paracellular pathway. H. pylori and bacterial antigens reach the lamina propria. For example, VacA can bind here to fibronectin in the extracellular matrix. (I) VacA also exhibits suppressive effects on immune cell function in vitro. VacA can interact with the integrin member β2 (CD18) on T-cells, which inhibits the transcription factor NFAT and IL-2 secretion, resulting in a blockade of T-cell activation and proliferation. Interestingly, it seems that CagA has some counteracting activities by activating NFAT via Ca2+-dependent calcineurin (Cn) signaling. (J) Urease B and VacA can also inhibit antigen presentation in B cells, possibly by interfering with antigen loading. (K) VacA was also reported to prevent phagosome-lysosome fusion in macrophages by recruiting the coat protein TACO (coronin 1) and can block integrin-linked kinase (ILK) to prevent the production of reactive oxygen species (ROS), thus supporting bacterial survival. (L) In addition, infection with H. pylori is accompanied by the formation of large homotypic aggregates of macrophages in a T4SS-dependent manner. This occurs through upregulation and recruitment of the intracellular adhesion molecule ICAM-1 to the cell surface, which then mediates aggregation via its ligand LFA-1, a signaling pathway that may regulate cell-cell interactions, inflammatory responses or inhibits bacterial uptake. (M) There are also various reports showing that H. pylori lipopolysaccharide (LPS) can activate the toll-like receptors TLR2 and/or TLR4 to stimulate NFκB and innate immune responses. (N) Recent data suggest that the H. pylori T4SS can also induce the host inflammasome in mice, which is regulating important innate immune functions. This requires the cooperative interaction among host innate immune receptors TLR2, NOD2, and NLRP3 as important regulators of caspase-1 and IL-1β activation in dendritic cells as indicated. For more details and references, see text and .
![Figure 1. Model of Helicobacter pylori-mediated contact with host protein receptors on epithelial and immune cells to trigger bacterial binding and/or downstream signal transduction events. The interplay between gastric epithelial and various types of immune cells with bacterial pathogenicity factors modulates multiple host responses during the course of infection as indicated. (A) H. pylori expresses several adhesins, some of which can bind to a host protein receptor. One example is the AlpA and AlpB adhesins binding to the matrix protein laminin. Attached H. pylori or those swimming in the mucus can secrete virulence factors into the medium including VacA and urease. VacA is a pore-forming toxin and can bind to various host surface receptors such as the RPTP tyrosine phosphatases. Internalization of VacA into cells leads to the formation of large vacuoles and gastric damage, a hallmark of the ulceration process. VacA can also trigger p38 MAP kinase activation, nuclear responses and mitochondria-associated apoptosis. (B) The H. pylori urease complex has an important function in buffering the acidic pH in the human stomach. However, urease B can also bind directly to the CD74 [MHC-II (class II major histocompatibility complex)-associated invariant chain] receptor on host cells, possibly activating the pro-inflammatory transcription factor NFκB and IL-8 release. Another receptor, CD46, acts as a bactericidal factor as it can bind to the urease A subunit and inhibits H. pylori urease activity. (C) After adherence, H. pylori can translocate effector molecules, such as CagA and peptidoglycan, into the host cell using a type IV secretion system (T4SS)-dependent process. Peptidoglycan binds to the intracellular receptor NOD1, activating transcription factors NFκB or IRF7 to stimulate the secretion of IL-8 or interferon-γ (IFNγ), respectively. (D) Injection of CagA requires various indicated T4SS pilus components and a host protein receptor, integrin β1. Since integrins are normally basolateral receptors, it is not yet clear if injection of CagA appears at apical or basolateral surfaces. However, injected CagA can interact with a number of host cell signaling molecules to trigger several signaling cascades as shown. For example, CagA can bind to PAR-1 and E-cadherin, possibly affecting cell polarity. CagA also contributes to sustained NFκB activity, inhibition of gastric acid production and cell elongation by targeting the actin-binding protein cortactin. (E) The H. pylori T4SS can also activate a number of receptor tyrosine kinases (RTKs) including EGFR, ErbB2, ErbB3 and c-Met which play various roles as indicated. Some yet undefined inhibitory activities on EGFR activation and wound healing have been attributed to VacA. (F) H. pylori targets the glycoprotein receptor GP130 using CagA (phosphorylated by Src and Abl kinases) to activate signal transducer and activation of transcription (STAT) signaling. (G) A novel CagL→integrin αvβ5 signaling complex was characterized to trigger gastrin expression. CagL can also bind to another integrin member, αvβ3, but the resulting downstream signaling is not yet clear. (H) Targeting of tight junctions and E-cadherin-based adherens junctions by the serine protease HtrA and CagA contribute to the disruption of the epithelial barrier. These events may cause leakage of nutrients into the gastric lumen and the ability of H. pylori to cross the epithelial layer by a paracellular pathway. H. pylori and bacterial antigens reach the lamina propria. For example, VacA can bind here to fibronectin in the extracellular matrix. (I) VacA also exhibits suppressive effects on immune cell function in vitro. VacA can interact with the integrin member β2 (CD18) on T-cells, which inhibits the transcription factor NFAT and IL-2 secretion, resulting in a blockade of T-cell activation and proliferation. Interestingly, it seems that CagA has some counteracting activities by activating NFAT via Ca2+-dependent calcineurin (Cn) signaling. (J) Urease B and VacA can also inhibit antigen presentation in B cells, possibly by interfering with antigen loading. (K) VacA was also reported to prevent phagosome-lysosome fusion in macrophages by recruiting the coat protein TACO (coronin 1) and can block integrin-linked kinase (ILK) to prevent the production of reactive oxygen species (ROS), thus supporting bacterial survival. (L) In addition, infection with H. pylori is accompanied by the formation of large homotypic aggregates of macrophages in a T4SS-dependent manner. This occurs through upregulation and recruitment of the intracellular adhesion molecule ICAM-1 to the cell surface, which then mediates aggregation via its ligand LFA-1, a signaling pathway that may regulate cell-cell interactions, inflammatory responses or inhibits bacterial uptake. (M) There are also various reports showing that H. pylori lipopolysaccharide (LPS) can activate the toll-like receptors TLR2 and/or TLR4 to stimulate NFκB and innate immune responses. (N) Recent data suggest that the H. pylori T4SS can also induce the host inflammasome in mice, which is regulating important innate immune functions. This requires the cooperative interaction among host innate immune receptors TLR2, NOD2, and NLRP3 as important regulators of caspase-1 and IL-1β activation in dendritic cells as indicated. For more details and references, see text and Table 1.](/cms/asset/f488842f-fefc-449c-84fc-3bdd43c2ee82/kgmi_a_10927001_f0001.gif)
