Статті в журналах: "Cag Type IV Secretion System"

1

Busler, Valerie J., Victor J. Torres, Mark S. McClain, Oscar Tirado, David B. Friedman, and Timothy L. Cover. "Protein-Protein Interactions among Helicobacter pylori Cag Proteins." Journal of Bacteriology 188, no. 13 (July 1, 2006): 4787–800. http://dx.doi.org/10.1128/jb.00066-06.

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ABSTRACT Many Helicobacter pylori isolates contain a 40-kb region of chromosomal DNA known as the cag pathogenicity island (PAI). The risk for development of gastric cancer or peptic ulcer disease is higher among humans infected with cag PAI-positive H. pylori strains than among those infected with cag PAI-negative strains. The cag PAI encodes a type IV secretion system that translocates CagA into gastric epithelial cells. To identify Cag proteins that are expressed by H. pylori during growth in vitro, we compared the proteomes of a wild-type H. pylori strain and an isogenic cag PAI deletion mutant using two-dimensional difference gel electrophoresis (2D-DIGE) in multiple pH ranges. Seven Cag proteins were identified by this approach. We then used a yeast two-hybrid system to detect potential protein-protein interactions among 14 Cag proteins. One heterotypic interaction (CagY/7 with CagX/8) and two homotypic interactions (involving H. pylori VirB11/ATPase and Cag5) were similar to interactions previously reported to occur among homologous components of the Agrobacterium tumefaciens type IV secretion system. Other interactions involved Cag proteins that do not have known homologues in other bacterial species. Biochemical analysis confirmed selected interactions involving five of the proteins that were identified by 2D-DIGE. Protein-protein interactions among Cag proteins are likely to have an important role in the assembly of the H. pylori type IV secretion apparatus.

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Pinto-Santini, Delia M., and Nina R. Salama. "Cag3 Is a Novel Essential Component of the Helicobacter pylori Cag Type IV Secretion System Outer Membrane Subcomplex." Journal of Bacteriology 191, no. 23 (October 2, 2009): 7343–52. http://dx.doi.org/10.1128/jb.00946-09.

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ABSTRACT Helicobacter pylori strains harboring the cag pathogenicity island (PAI) have been associated with more severe gastric disease in infected humans. The cag PAI encodes a type IV secretion (T4S) system required for CagA translocation into host cells as well as induction of proinflammatory cytokines, such as interleukin-8 (IL-8). cag PAI genes sharing sequence similarity with T4S components from other bacteria are essential for Cag T4S function. Other cag PAI-encoded genes are also essential for Cag T4S, but lack of sequence-based or structural similarity with genes in existing databases has precluded a functional assignment for the encoded proteins. We have studied the role of one such protein, Cag3 (HP0522), in Cag T4S and determined Cag3 subcellular localization and protein interactions. Cag3 is membrane associated and copurifies with predicted inner and outer membrane Cag T4S components that are essential for Cag T4S as well as putative accessory factors. Coimmunoprecipitation and cross-linking experiments revealed specific interactions with HpVirB7 and CagM, suggesting Cag3 is a new component of the Cag T4S outer membrane subcomplex. Finally, lack of Cag3 lowers HpVirB7 steady-state levels, further indicating Cag3 makes a subcomplex with this protein.

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Kumar, Navin, Mohd Shariq, Rajesh Kumari, Rakesh K. Tyagi, and Gauranga Mukhopadhyay. "Cag Type IV Secretion System: CagI Independent Bacterial Surface Localization of CagA." PLoS ONE 8, no. 9 (September 10, 2013): e74620. http://dx.doi.org/10.1371/journal.pone.0074620.

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Cover, Timothy L., D. Borden Lacy, and Melanie D. Ohi. "The Helicobacter pylori Cag Type IV Secretion System." Trends in Microbiology 28, no. 8 (August 2020): 682–95. http://dx.doi.org/10.1016/j.tim.2020.02.004.

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Couturier, Marc Roger, Elizabetta Tasca, Cesare Montecucco, and Markus Stein. "Interaction with CagF Is Required for Translocation of CagA into the Host via the Helicobacter pylori Type IV Secretion System." Infection and Immunity 74, no. 1 (January 2006): 273–81. http://dx.doi.org/10.1128/iai.74.1.273-281.2006.

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ABSTRACT Development of severe gastric diseases is strongly associated with those strains of Helicobacter pylori that contain the cag pathogenicity island (PAI) inserted into the chromosome. The cag PAI encodes a type IV secretion system that translocates the major disease-associated virulence protein, CagA, into the host epithelial cell. CagA then affects host signaling pathways, leading to cell elongations and inflammation. Since the precise mechanism by which the CagA toxin is translocated by the type IV secretion system remained elusive, we used fusion proteins and immunoprecipitation studies to identify CagA-interacting secretion components. Here we demonstrate that CagA, in addition to other yet-unidentified proteins, interacts with CagF, presumably at the inner bacterial membrane. This interaction is required for CagA translocation, since an isogenic nonpolar cagF mutant was translocation deficient. Our results suggest that CagF may be a protein with unique chaperone-like function that is involved in the early steps of CagA recognition and delivery into the type IV secretion channel.

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Kutter, Stefan, Renate Buhrdorf, Jürgen Haas, Wulf Schneider-Brachert, Rainer Haas, and Wolfgang Fischer. "Protein Subassemblies of the Helicobacter pylori Cag Type IV Secretion System Revealed by Localization and Interaction Studies." Journal of Bacteriology 190, no. 6 (January 4, 2008): 2161–71. http://dx.doi.org/10.1128/jb.01341-07.

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ABSTRACT Type IV secretion systems are possibly the most versatile protein transport systems in gram-negative bacteria, with substrates ranging from small proteins to large nucleoprotein complexes. In many cases, such as the cag pathogenicity island of Helicobacter pylori, genes encoding components of a type IV secretion system have been identified due to their sequence similarities to prototypical systems such as the VirB system of Agrobacterium tumefaciens. The Cag type IV secretion system contains at least 14 essential apparatus components and several substrate translocation and auxiliary factors, but the functions of most components cannot be inferred from their sequences due to the lack of similarities. In this study, we have performed a comprehensive sequence analysis of all essential or auxiliary Cag components, and we have used antisera raised against a subset of components to determine their subcellular localization. The results suggest that the Cag system contains functional analogues to all VirB components except VirB5. Moreover, we have characterized mutual stabilization effects and performed a comprehensive yeast two-hybrid screening for potential protein-protein interactions. Immunoprecipitation studies resulted in identification of a secretion apparatus subassembly at the outer membrane. Combining these data, we provide a first low-resolution model of the Cag type IV secretion apparatus.

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Terradot, Laurent, and Gabriel Waksman. "Architecture of the Helicobacter pylori Cag-type IV secretion system." FEBS Journal 278, no. 8 (February 25, 2011): 1213–22. http://dx.doi.org/10.1111/j.1742-4658.2011.08037.x.

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Chung, Jeong Min, Michael J. Sheedlo, Anne M. Campbell, Neha Sawhney, Arwen E. Frick-Cheng, D. Borden Lacy, Timothy L. Cover, and Melanie D. Ohi. "Structure of the Helicobacter pylori Cag Type IV Secretion System." Biophysical Journal 118, no. 3 (February 2020): 295a. http://dx.doi.org/10.1016/j.bpj.2019.11.1671.

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Jurik, Angela, Elisabeth Haußer, Stefan Kutter, Isabelle Pattis, Sandra Praßl, Evelyn Weiss та Wolfgang Fischer. "The Coupling Protein Cagβ and Its Interaction Partner CagZ Are Required for Type IV Secretion of the Helicobacter pylori CagA Protein". Infection and Immunity 78, № 12 (27 вересня 2010): 5244–51. http://dx.doi.org/10.1128/iai.00796-10.

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ABSTRACT Bacterial type IV secretion systems are macromolecule transporters with essential functions for horizontal gene transfer and for symbiotic and pathogenic interactions with eukaryotic host cells. Helicobacter pylori, the causative agent of type B gastritis, peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma, uses the Cag type IV secretion system to inject its effector protein CagA into gastric cells. This protein translocation results in altered host cell gene expression profiles and cytoskeletal rearrangements, and it has been linked to cancer development. Interactions of CagA with host cell proteins have been studied in great detail, but little is known about the molecular details of CagA recognition as a type IV secretion substrate or of the translocation process. Apart from components of the secretion apparatus, we previously identified several CagA translocation factors that are either required for or support CagA translocation. To identify protein-protein interactions between these translocation factors, we used a yeast two-hybrid approach comprising all cag pathogenicity island genes. Among several other interactions involving translocation factors, we found a strong interaction between the coupling protein homologue Cagβ (HP0524) and the Cag-specific translocation factor CagZ (HP0526). We show that CagZ has a stabilizing effect on Cagβ, and we demonstrate protein-protein interactions between the cytoplasmic part of Cagβ and CagA and between CagZ and Cagβ, using immunoprecipitation and pull-down assays. Together, our data suggest that these interactions represent a substrate-translocation factor complex at the bacterial cytoplasmic membrane.

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Chang, Yi-Wei, Carrie L. Shaffer, Lee A. Rettberg, Debnath Ghosal, and Grant J. Jensen. "In Vivo Structures of the Helicobacter pylori cag Type IV Secretion System." Cell Reports 23, no. 3 (April 2018): 673–81. http://dx.doi.org/10.1016/j.celrep.2018.03.085.

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11

Lettl, Clara, and Wolfgang Fischer. "Export von Gefahrgut: Helicobacter pylori und sein CagA-Protein." BIOspektrum 26, no. 6 (October 14, 2020): 597–99. http://dx.doi.org/10.1007/s12268-020-1454-7.

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Abstract Pathogenic bacteria often utilize type IV secretion systems to interact with host cells and to modify their microenvironment in a favourable way. The human pathogen Helicobacter pylori produces such a system to inject only a single protein, CagA, into gastric cells, but this injection represents a major risk factor for gastric cancer development. Here, we discuss the unusual structure of the Cag secretion nanomachine and other features that make it unique among bacterial protein transporters.

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Sheedlo, Michael J., Melanie D. Ohi, D. Borden Lacy, and Timothy L. Cover. "Molecular architecture of bacterial type IV secretion systems." PLOS Pathogens 18, no. 8 (August 11, 2022): e1010720. http://dx.doi.org/10.1371/journal.ppat.1010720.

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Bacterial type IV secretion systems (T4SSs) are a versatile group of nanomachines that can horizontally transfer DNA through conjugation and deliver effector proteins into a wide range of target cells. The components of T4SSs in gram-negative bacteria are organized into several large subassemblies: an inner membrane complex, an outer membrane core complex, and, in some species, an extracellular pilus. Cryo-electron tomography has been used to define the structures of T4SSs in intact bacteria, and high-resolution structural models are now available for isolated core complexes from conjugation systems, the Xanthomonas citri T4SS, the Helicobacter pylori Cag T4SS, and the Legionella pneumophila Dot/Icm T4SS. In this review, we compare the molecular architectures of these T4SSs, focusing especially on the structures of core complexes. We discuss structural features that are shared by multiple T4SSs as well as evolutionary strategies used for T4SS diversification. Finally, we discuss how structural variations among T4SSs may confer specialized functional properties.

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Skoog, Emma C., Miriam E. Martin, Roberto M. Barrozo, Lori M. Hansen, Lucy P. Cai, Seung-Joo Lee, Joseph M. Benoun, Stephen J. McSorley, and Jay V. Solnick. "Maintenance of Type IV Secretion Function During Helicobacter pylori Infection in Mice." mBio 11, no. 6 (December 22, 2020): e03147-20. http://dx.doi.org/10.1128/mbio.03147-20.

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ABSTRACTThe Helicobacter pylori type IV secretion system (T4SS) encoded on the cag pathogenicity island (cagPAI) secretes the CagA oncoprotein and other effectors into the gastric epithelium. During murine infection, T4SS function is lost in an immune-dependent manner, typically as a result of in-frame recombination in the middle repeat region of cagY, though single nucleotide polymorphisms (SNPs) in cagY or in other essential genes may also occur. Loss of T4SS function also occurs in gerbils, nonhuman primates, and humans, suggesting that it is biologically relevant and not simply an artifact of the murine model. Here, we sought to identify physiologically relevant conditions under which T4SS function is maintained in the murine model. We found that loss of H. pylori T4SS function in mice was blunted by systemic Salmonella coinfection and completely eliminated by dietary iron restriction. Both have epidemiologic parallels in humans, since H. pylori strains from individuals in developing countries, where iron deficiency and systemic infections are common, are also more often cagPAI+ than strains from developed countries. These results have implications for our fundamental understanding of the cagPAI and also provide experimental tools that permit the study of T4SS function in the murine model.IMPORTANCE The type IV secretion system (T4SS) is the major Helicobacter pylori virulence factor, though its function is lost during murine infection. Loss of function also occurs in gerbils and in humans, suggesting that it is biologically relevant, but the conditions under which T4SS regulation occurs are unknown. Here, we found that systemic coinfection with Salmonella and iron deprivation each promote retention of T4SS function. These results improve our understanding of the cag pathogenicity island (cagPAI) and provide experimental tools that permit the study of T4SS function in the murine model.

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Wroblewski, Lydia E., Eunyoung Choi, Christine Petersen, Alberto G. Delgado, M. Blanca Piazuelo, Judith Romero-Gallo, Tyler L. Lantz, et al. "Targeted mobilization of Lrig1+ gastric epithelial stem cell populations by a carcinogenic Helicobacter pylori type IV secretion system." Proceedings of the National Academy of Sciences 116, no. 39 (September 5, 2019): 19652–58. http://dx.doi.org/10.1073/pnas.1903798116.

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Helicobacter pylori-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the cag type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within H. pylori-infected gastric mucosa. Lineage tracing was induced in Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) mice that were uninfected or subsequently infected with cag+H. pylori or an isogenic cagE− mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) H. pylori for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the cagE− mutant. WT H. pylori-infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT H. pylori. In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic H. pylori infection stimulates Lrig1-expressing progenitor cells in a cag-dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.

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Kumari, Rajesh, Mohd Shariq, Shivani Sharma, Ajay Kumar, and Gauranga Mukhopadhyay. "CagW, a VirB6 homologue interacts with Cag-type IV secretion system substrate CagA in Helicobacter pylori." Biochemical and Biophysical Research Communications 515, no. 4 (August 2019): 712–18. http://dx.doi.org/10.1016/j.bbrc.2019.06.013.

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Andrzejewska, Joanna, Sae Kyung Lee, Patrick Olbermann, Nina Lotzing, Elena Katzowitsch, Bodo Linz, Mark Achtman, Clarence I. Kado, Sebastian Suerbaum, and Christine Josenhans. "Characterization of the Pilin Ortholog of the Helicobacter pylori Type IV cag Pathogenicity Apparatus, a Surface-Associated Protein Expressed during Infection." Journal of Bacteriology 188, no. 16 (August 15, 2006): 5865–77. http://dx.doi.org/10.1128/jb.00060-06.

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ABSTRACT The Helicobacter pylori cag pathogenicity island (cag PAI) encodes components of a type IV secretion system (T4SS) involved in host interaction and pathogenicity. Previously, seven cag PAI proteins were identified as homologs of Agrobacterium tumefaciens Vir proteins, which form a paradigm T4SS. The T pilus composed of the processed VirB2 pilin is an external structural part of the A. tumefaciens T4SS. In H. pylori, cag-dependent assembly of pili has not been observed so far, nor has a pilin (VirB2) ortholog been characterized. We have here identified, using a motif-based search, an H. pylori cag island protein (HP0546) that possesses sequence and predicted structural similarities to VirB2-like pilins of other T4SSs. The HP0546 protein displays interstrain variability in its terminal domains. HP0546 was expressed as a FLAG-tagged fusion protein in Escherichia coli, A. tumefaciens, and H. pylori and was detected as either two or three bands of different molecular masses in the insoluble fraction, indicating protein processing. As reported previously, isogenic H. pylori mutants in the putative cag pilin gene had reduced abilities to induce cag PAI-dependent interleukin-8 secretion in gastric epithelial cells. Fractionation analysis of H. pylori, using a specific antiserum raised against an N-terminal HP0546 peptide, showed that the protein is partially surface exposed and that its surface localization depended upon an intact cag system. By immunoelectron microscopy, HP0546 was localized in surface appendages, with surface exposure of an N-terminal epitope. Pronounced strain-to-strain variability of this predicted surface-exposed part of HP0546 indicates a strong selective pressure for variation in vivo.

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Lu, Jacky, Kathryn P. Haley, Jamisha D. Francis, Miriam A. Guevara, Ryan S. Doster, Kelly M. Craft, Rebecca E. Moore, et al. "The Innate Immune Glycoprotein Lactoferrin Represses the Helicobacter pylori cag Type IV Secretion System." ChemBioChem 22, no. 18 (July 8, 2021): 2783–90. http://dx.doi.org/10.1002/cbic.202100249.

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Rohde, Manfred, Jürgen Püls, Renate Buhrdorf, Wolfgang Fischer, and Rainer Haas. "A novel sheathed surface organelle of the Helicobacter pylori cag type IV secretion system." Molecular Microbiology 49, no. 1 (May 30, 2003): 219–34. http://dx.doi.org/10.1046/j.1365-2958.2003.03549.x.

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Gaddy, J. A., and T. L. Cover. "High Resolution Electron Microscopy Analysis of the Helicobacter pylori Cag Type IV Secretion System." Microscopy and Microanalysis 19, S2 (August 2013): 224–25. http://dx.doi.org/10.1017/s1431927613003115.

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Pham, Kieu Thuy, Evelyn Weiss, Luisa F. Jiménez Soto, Ute Breithaupt, Rainer Haas, and Wolfgang Fischer. "CagI Is an Essential Component of the Helicobacter pylori Cag Type IV Secretion System and Forms a Complex with CagL." PLoS ONE 7, no. 4 (April 6, 2012): e35341. http://dx.doi.org/10.1371/journal.pone.0035341.

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Bourzac, Kevin M., Laura A. Satkamp, and Karen Guillemin. "The Helicobacter pylori cag Pathogenicity Island Protein CagN Is a Bacterial Membrane-Associated Protein That Is Processed at Its C Terminus." Infection and Immunity 74, no. 5 (May 2006): 2537–43. http://dx.doi.org/10.1128/iai.74.5.2537-2543.2006.

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ABSTRACT Helicobacter pylori infects nearly half the world's population and is associated with a spectrum of gastric maladies. Infections with cytotoxin-associated gene pathogenicity island (cag PAI)-containing strains are associated with an increased risk for gastric cancer. The cag PAI contains genes encoding a type IV secretion system (T4SS) and a delivered effector, CagA, that becomes tyrosine phosphorylated upon delivery into host cells and initiates changes in cell signaling. Although some cag PAI genes have been shown to be required for CagA delivery, a subset of which are homologues of T4SS genes from Agrobacterium tumefaciens, the majority have no known function or homologues. We have performed a detailed investigation of one such cag PAI protein, CagN, which is encoded by the gene HP0538. Our results show that CagN is not delivered into host cells and instead is associated with the bacterial membrane. We demonstrate that CagN is cleaved at its C terminus by a mechanism that is independent of other cag PAI proteins. Finally, we show that a ΔcagN mutant is not impaired in its ability to deliver CagA to gastric epithelial cells and initiate cell elongation.

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Tegtmeyer, Nicole, Silja Wessler, and Steffen Backert. "Role of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis." FEBS Journal 278, no. 8 (February 25, 2011): 1190–202. http://dx.doi.org/10.1111/j.1742-4658.2011.08035.x.

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23

Sierra, Johanna C., Stuart Hobbs, Rupesh Chaturvedi, Fang Yan, Keith T. Wilson, Richard M. Peek, and D. Brent Polk. "Induction of COX-2 expression by Helicobacter pylori is mediated by activation of epidermal growth factor receptor in gastric epithelial cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 305, no. 2 (July 15, 2013): G196—G203. http://dx.doi.org/10.1152/ajpgi.00495.2012.

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Chronic infection of the gastric mucosa by Helicobacter pylori is associated with an increased risk of developing gastric cancer; however, the vast majority of infected individuals never develop this disease. One H. pylori virulence factor that increases gastric cancer risk is the cag pathogenicity island, which encodes a bacterial type IV secretion system. Cyclooxygenase-2 (COX-2) expression is induced by proinflammatory stimuli, leading to increased prostaglandin E2 (PGE2) secretion by gastric epithelial cells. COX-2 expression is increased in gastric tissue from H. pylori -infected persons. H. pylori also activates the epidermal growth factor receptor (EGFR) in gastric epithelial cells. We now demonstrate that H. pylori -induced activation of COX-2 in gastric cells is dependent upon EGFR activation, and that a functional cag type IV secretion system and direct bacterial contact are necessary for full induction of COX-2 by gastric epithelial cells. PGE2 secretion is increased in cells infected with H. pylori , and this induction is dependent on a functional EGFR. Increased apoptosis in response to H. pylori occurs in cells treated with a COX-2 inhibitor, as well as COX-2−/− cells, indicating that COX-2 expression promotes cell survival. In vivo, COX-2 induction by H. pylori is significantly reduced in mice deficient for EGFR activation compared with wild-type mice with a fully functional receptor. Collectively, these findings indicate that aberrant activation of the EGFR-COX-2 axis may lower the threshold for carcinogenesis associated with chronic H. pylori infection.

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Mane, S. P., M. G. Dominguez-Bello, M. J. Blaser, B. W. Sobral, R. Hontecillas, J. Skoneczka, S. K. Mohapatra, et al. "Host-Interactive Genes in Amerindian Helicobacter pylori Diverge from Their Old World Homologs and Mediate Inflammatory Responses." Journal of Bacteriology 192, no. 12 (April 16, 2010): 3078–92. http://dx.doi.org/10.1128/jb.00063-10.

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ABSTRACT Helicobacter pylori is the dominant member of the gastric microbiota and has been associated with an increased risk of gastric cancer and peptic ulcers in adults. H. pylori populations have migrated and diverged with human populations, and health effects vary. Here, we describe the whole genome of the cag-positive strain V225d, cultured from a Venezuelan Piaroa Amerindian subject. To gain insight into the evolution and host adaptation of this bacterium, we undertook comparative H. pylori genomic analyses. A robust multiprotein phylogenetic tree reflects the major human migration out of Africa, across Europe, through Asia, and into the New World, placing Amerindian H. pylori as a particularly close sister group to East Asian H. pylori. In contrast, phylogenetic analysis of the host-interactive genes vacA and cagA shows substantial divergence of Amerindian from Old World forms and indicates new genotypes (e.g., VacA m3) involving these loci. Despite deletions in CagA EPIYA and CRPIA domains, V225d stimulates interleukin-8 secretion and the hummingbird phenotype in AGS cells. However, following a 33-week passage in the mouse stomach, these phenotypes were lost in isolate V225-RE, which had a 15-kb deletion in the cag pathogenicity island that truncated CagA and eliminated some of the type IV secretion system genes. Thus, the unusual V225d cag architecture was fully functional via conserved elements, but the natural deletion of 13 cag pathogenicity island genes and the truncation of CagA impaired the ability to induce inflammation.

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Gaddy, Jennifer A., Jana N. Radin, John T. Loh, M. Blanca Piazuelo, Thomas E. Kehl-Fie, Alberto G. Delgado, Florin T. Ilca, et al. "The Host Protein Calprotectin Modulates the Helicobacter pylori cag Type IV Secretion System via Zinc Sequestration." PLoS Pathogens 10, no. 10 (October 16, 2014): e1004450. http://dx.doi.org/10.1371/journal.ppat.1004450.

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Johnson, Elizabeth M., Jennifer A. Gaddy, Bradley J. Voss, Ewa E. Hennig, and Timothy L. Cover. "Genes Required for Assembly of Pili Associated with the Helicobacter pylori cag Type IV Secretion System." Infection and Immunity 82, no. 8 (June 2, 2014): 3457–70. http://dx.doi.org/10.1128/iai.01640-14.

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ABSTRACTHelicobacter pyloricauses numerous alterations in gastric epithelial cells through processes that are dependent on activity of thecagtype IV secretion system (T4SS). Filamentous structures termed “pili” have been visualized at the interface betweenH. pyloriand gastric epithelial cells, and previous studies suggested that pilus formation is dependent on the presence of thecagpathogenicity island (PAI). Thus far, there has been relatively little effort to identify specific genes that are required for pilus formation, and the role of pili in T4SS function is unclear. In this study, we selected 7 genes in thecagPAI that are known to be required for T4SS function and investigated whether these genes were required for pilus formation.cagT,cagX,cagV,cagM, andcag3mutants were defective in both T4SS function and pilus formation; complemented mutants regained T4SS function and the capacity for pilus formation.cagYandcagCmutants were defective in T4SS function but retained the capacity for pilus formation. These results define a set ofcagPAI genes that are required for both pilus biogenesis and T4SS function and reveal that these processes can be uncoupled in specific mutant strains.

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Roberts, Jacquelyn R., Sirena C. Tran, Arwen E. Frick-Cheng, Kaeli N. Bryant, Chiamaka D. Okoye, W. Hayes McDonald, Timothy L. Cover, and Melanie D. Ohi. "Subdomains of theHelicobacter pyloriCag T4SS outer membrane core complex exhibit structural independence." Life Science Alliance 7, no. 6 (April 17, 2024): e202302560. http://dx.doi.org/10.26508/lsa.202302560.

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TheHelicobacter pyloriCag type IV secretion system (Cag T4SS) has an important role in the pathogenesis of gastric cancer. The Cag T4SS outer membrane core complex (OMCC) is organized into three regions: a 14-fold symmetric outer membrane cap (OMC) composed of CagY, CagX, CagT, CagM, and Cag3; a 17-fold symmetric periplasmic ring (PR) composed of CagY and CagX; and a stalk with unknown composition. We investigated how CagT, CagM, and a conserved antenna projection (AP) region of CagY contribute to the structural organization of the OMCC. Single-particle cryo-EM analyses showed that complexes purified from ΔcagTor ΔcagMmutants no longer had organized OMCs, but the PRs remained structured. OMCCs purified from a CagY antenna projection mutant (CagY∆AP) were structurally similar to WT OMCCs, except for the absence of the α-helical antenna projection. These results indicate that CagY and CagX are sufficient for maintaining a stable PR, but the organization of the OMC requires CagY, CagX, CagM, and CagT. Our results highlight an unexpected structural independence of two major subdomains of the Cag T4SS OMCC.

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Rieder, Gabriele, Juanita L. Merchant, and Rainer Haas. "Helicobacter pylori cag-Type IV Secretion System Facilitates Corpus Colonization to Induce Precancerous Conditions in Mongolian Gerbils." Gastroenterology 128, no. 5 (May 2005): 1229–42. http://dx.doi.org/10.1053/j.gastro.2005.02.064.

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Noto, Jennifer M., Jennifer Gaddy, Josephine Y. Lee, M. Blanca Piazuelo, David Friedman, Judith Romero-Gallo, Shumin Tan, et al. "617 Iron Deficiency Amplifies the Pathogenic Potential of Carcinogenic cag+ Helicobacter pylori via Enhancing Function of the cag Type IV Secretion System." Gastroenterology 142, no. 5 (May 2012): S—121. http://dx.doi.org/10.1016/s0016-5085(12)60457-0.

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Ogura, Keiji, Shin Maeda, Masafumi Nakao, Takeshi Watanabe, Mayumi Tada, Toshimasa Kyutoku, Haruhiko Yoshida, Yasushi Shiratori, and Masao Omata. "Virulence Factors of Helicobacter pylori Responsible for Gastric Diseases in Mongolian Gerbil." Journal of Experimental Medicine 192, no. 11 (December 4, 2000): 1601–10. http://dx.doi.org/10.1084/jem.192.11.1601.

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Helicobacter pylori infection induces various gastroduodenal diseases. We examined the role of two genes, vacA and cagE, in the gastric pathogenesis induced by H. pylori using a long-term (62 wk) animal model. Reportedly, both genes are associated with the virulence of H. pylori: vacA encodes vacuolating cytotoxin, and cagE, with other genes in the cag pathogenicity islands, encodes a type IV secretion system. Mongolian gerbils were challenged in this study by a wild-type TN2 strain and its isogenic mutants of cagE or vacA. The wild-type and vacA mutants induced severe gastritis, whereas cagE mutants induced far milder changes. Gastric ulcer was induced at the highest rate (22/23) by the wild-type TN2, followed by the vacA mutant (19/28). No ulcer was found in the gerbils infected with the cagE mutant (0/27) or in controls (0/27). Intestinal metaplasia was also found in the gerbils infected with the wild-type (14/23) or vacA mutant (15/28). Gastric cancer developed in one gerbil with wild-type infection and in one with vacA mutant infection. In conclusion, the knocking out of the cagE gene deprived wild-type H. pylori of the pathogenicity for gastritis and gastric ulcer, suggesting that the secretion system encoded by cag pathogenicity island genes plays an essential role.

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Hilleringmann, Markus, Werner Pansegrau, Michael Doyle, Susan Kaufman, Mary Lee MacKichan, Claudia Gianfaldoni, Paolo Ruggiero та Antonello Covacci. "Inhibitors of Helicobacter pylori ATPase Cagα block CagA transport and cag virulence". Microbiology 152, № 10 (1 жовтня 2006): 2919–30. http://dx.doi.org/10.1099/mic.0.28984-0.

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With the steadily increasing occurrence of antibiotic resistance in bacteria, there is a great need for new antibacterial compounds. The approach described here involves targeting virulence-related bacterial type IV secretion systems (TFSSs) with small-molecule inhibitors. The cag TFSS of Helicobacter pylori was chosen as a model, and novel inhibitors directed against the cag VirB11-type ATPase Cagα were identified. The cag genes encode proteins that are components of a contact-dependent secretion system used by the bacterium to translocate the effector molecule CagA into host cells. Translocated CagA is associated with severe gastritis, and carcinoma. Furthermore, functional TFSSs and immunodominant CagA play a role in interleukin (IL)-8 induction, which is an important factor for chronic inflammation. Inhibitors of Cagα were identified by high-throughput screening of chemical libraries that comprised 524 400 small molecules. The ATPase activity of Cagα was inhibited by the selected compounds in an in vitro enzymic assay using the purified enzyme. The most active compound, CHIR-1, reduced TFSS function to an extent that cellular effects on AGS cells mediated by CagA were virtually undetectable, while reduced levels of IL-8 induction were observed. Gastric colonization by CHIR-1-pre-treated bacteria was found to be impaired in a dose-dependent manner using a mouse model of infection. Small-molecule Cagα inhibitors, the first described inhibitors of a TFSS, are potential candidates for the development of new antibacterial compounds that may lead to alternative medical treatments. The compounds are expected to impose weak selective pressure, since they target virulence functions. Moreover, the targeted virulence protein is conserved in a variety of bacterial pathogens. Additionally, TFSS inhibitors are potent tools to study the biology of TFSSs.

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Höppner, Christoph, Zhenying Liu, Natalie Domke, Andrew N. Binns, and Christian Baron. "VirB1 Orthologs from Brucella suis and pKM101 Complement Defects of the Lytic Transglycosylase Required for Efficient Type IV Secretion from Agrobacterium tumefaciens." Journal of Bacteriology 186, no. 5 (March 1, 2004): 1415–22. http://dx.doi.org/10.1128/jb.186.5.1415-1422.2004.

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ABSTRACT Type IV secretion systems mediate conjugative plasmid transfer as well as the translocation of virulence factors from various gram-negative pathogens to eukaryotic host cells. The translocation apparatus consists of 9 to 12 components, and the components from different organisms are believed to have similar functions. However, orthologs to proteins of the prototypical type IV system, VirB of Agrobacterium tumefaciens, typically share only 15 to 30% identical amino acids, and functional complementation between components of different type IV secretion systems has not been achieved. We here report a heterologous complementation in the case of A. tumefaciens virB1 defects with its orthologs from Brucella suis (VirB1s) and the IncN plasmid pKM101 (TraL). In contrast, expression of the genes encoding the VirB1 orthologs from the IncF plasmid (open reading frame 169) and from the Helicobacter pylori cag pathogenicity island (HP0523) did not complement VirB1 functions. The complementation of VirB1 activity was assessed by T-pilus formation, by tumor formation on wounded plants, by IncQ plasmid transfer, and by IncQ plasmid recipient assay. Replacement of the key active-site Glu residue by Ala abolished the complementation by VirB1 from B. suis and by TraL, demonstrating that heterologous complementation requires an intact lytic transglycosylase active site. In contrast, the VirB1 active-site mutant from A. tumefaciens retained considerable residual activity in various activity assays, implying that this protein exerts additional effects during the type IV secretion process.

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Buhrdorf, Renate, Cornelia Förster, Rainer Haas, and Wolfgang Fischer. "Topological analysis of a putative virB8 homologue essential for the cag type IV secretion system in Helicobacter pylori." International Journal of Medical Microbiology 293, no. 2-3 (January 2003): 213–17. http://dx.doi.org/10.1078/1438-4221-00260.

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Koelblen, Thomas, Célia Bergé, Mickaël V. Cherrier, Karl Brillet, Luisa Jimenez-Soto, Lionel Ballut, Junichi Takagi та ін. "Molecular dissection of protein-protein interactions between integrin α5β1 and the Helicobacter pylori Cag type IV secretion system". FEBS Journal 284, № 23 (12 листопада 2017): 4143–57. http://dx.doi.org/10.1111/febs.14299.

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Lu, Jacky, Kathryn P. Haley, Jamisha D. Francis, Miriam A. Guevara, Ryan S. Doster, Kelly M. Craft, Rebecca E. Moore, et al. "Cover Feature: The Innate Immune Glycoprotein Lactoferrin Represses the Helicobacter pylori cag Type IV Secretion System (ChemBioChem 18/2021)." ChemBioChem 22, no. 18 (July 29, 2021): 2737. http://dx.doi.org/10.1002/cbic.202100349.

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Varga, M. G., C. L. Shaffer, J. C. Sierra, G. Suarez, M. B. Piazuelo, M. E. Whitaker, J. Romero-Gallo, et al. "Pathogenic H elicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system." Oncogene 35, no. 48 (May 9, 2016): 6262–69. http://dx.doi.org/10.1038/onc.2016.158.

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Varga, Matthew G., M. Blanca Piazuelo, Judith Romero-Gallo, Alberto G. Delgado, Giovanni Suarez, Morgan E. Whitaker, Uma S. Krishna, et al. "TLR9 activation suppresses inflammation in response to Helicobacter pylori infection." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 5 (November 1, 2016): G852—G858. http://dx.doi.org/10.1152/ajpgi.00175.2016.

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Helicobacter pylori ( H. pylori) induces chronic gastritis in humans, and infection can persist for decades. One H. pylori strain-specific constituent that augments disease risk is the cag pathogenicity island. The cag island encodes a type IV secretion system (T4SS) that translocates DNA into host cells. Toll-like receptor 9 (TLR9) is an innate immune receptor that detects hypo-methylated CpG DNA motifs. In this study, we sought to define the role of the H. pylori cag T4SS on TLR9-mediated responses in vivo. H. pylori strain PMSS1 or its cagE − mutant, which fails to assemble a T4SS, were used to infect wild-type or Tlr9 −/− C57BL/6 mice. PMSS1-infected Tlr9 −/− mice developed significantly higher levels of inflammation, despite similar levels of colonization density, compared with PMSS1-infected wild-type mice. These changes were cag dependent, as both mouse genotypes infected with the cagE − mutant only developed minimal inflammation. Tlr9 −/− genotypes did not alter the microbial phenotypes of in vivo-adapted H. pylori strains; therefore, we examined host immunological responses. There were no differences in levels of TH1 or TH2 cytokines in infected mice when stratified by host genotype. However, gastric mucosal levels of IL-17 were significantly increased in infected Tlr9 −/− mice compared with infected wild-type mice, and H. pylori infection of IL-17A −/− mice concordantly led to significantly decreased levels of gastritis. Thus loss of Tlr9 selectively augments the intensity of IL-17-driven immune responses to H. pylori in a cag T4SS-dependent manner. These results suggest that H. pylori utilizes the cag T4SS to manipulate the intensity of the host immune response.

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Bauer, Bianca, Stefan Moese, Sina Bartfeld, Thomas F. Meyer, and Matthias Selbach. "Analysis of Cell Type-Specific Responses Mediated by the Type IV Secretion System of Helicobacter pylori." Infection and Immunity 73, no. 8 (August 2005): 4643–52. http://dx.doi.org/10.1128/iai.73.8.4643-4652.2005.

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ABSTRACT Helicobacter pylori persistently infects the human stomach and can cause gastritis, gastric ulceration, and gastric cancer. The type IV secretion system (TFSS) of virulent H. pylori strains translocates the CagA protein, inducing the dephosphorylation of host cell proteins and leading to changes in the morphology or shape of AGS gastric epithelial cells. Furthermore, the TFSS is involved in the induction of proinflammatory cytokines. While the H. pylori genes required for TFSS function have been investigated systematically, little is known about possible host cell factors involved. We infected 19 different mammalian cell lines individually with H. pylori and analyzed CagA translocation, dephosphorylation of host cell proteins, chemokine secretion (interleukin-8 and macrophage inflammatory protein 2), and changes in cellular phenotypes. Our results demonstrate that not only bacterial but also host cell factors determine the cellular response to infection. The identification of such unknown host cell factors will add to our understanding of host-pathogen interactions and might help in the development of new therapeutic strategies.

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Reyes-Leon, Adriana, John C. Atherton, Richard H. Argent, J. L. Puente, and J. Torres. "Heterogeneity in the Activity of Mexican Helicobacter pylori Strains in Gastric Epithelial Cells and Its Association with Diversity in the cagA Gene." Infection and Immunity 75, no. 7 (April 16, 2007): 3445–54. http://dx.doi.org/10.1128/iai.01951-06.

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ABSTRACT Helicobacter pylori CagA is translocated into gastric epithelial cells by a type IV secretion system and interacts with the Src homology 2 phosphatase, altering cell morphology. Multiple EPIYA motifs in CagA are associated with increased activity in cells and with gastric cancer. The aim of this work was to study the heterogeneity in activity in cells of multiple H. pylori single colonies isolated from a single patient and its association with polymorphism in cagA. The presence of cagA, cagE, cagT, and cag10 was studied with 318 H. pylori isolates from the antra and corpora of 18 patients. AGS gastric epithelial cells were infected with 75 isolates, and interleukin-8 (IL-8) secretion, cytoskeletal changes, CagA translocation, and tyrosine phosphorylation were measured. The cagA 3′-variable region was sequenced for 30 isolates to determine the number and types of EPIYA motifs. Isolates from an individual stomach were usually genetically related and had quantitatively similar phenotypic effects on cells (IL-8 induction and cytoskeletal changes). However, strains from different patients with similar CagA EPIYA motif patterns varied widely in these phenotypes. Among isolates with an EPIYA-ABC pattern, the phenotype was variable: IL-8 induction ranged from 200 to 1,200 pg/ml, and morphological changes occurred in 20 to 70% of cells. In several cases, cagA sequence diversity appeared to explain the lack of CagA activity, as isolates with an EPIYA-ACC pattern or a modified B motif had reduced cell activity. cag pathogenicity island-positive H. pylori isolates displayed a high level of heterogeneity in the capacity to induce IL-8 secretion and morphological changes; an absent or modified B motif was associated with low activity.

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Tran, Cong Tri, Magali Garcia, Martine Garnier, Christophe Burucoa, and Charles Bodet. "Inflammatory signaling pathways induced by Helicobacter pylori in primary human gastric epithelial cells." Innate Immunity 23, no. 2 (December 5, 2016): 165–74. http://dx.doi.org/10.1177/1753425916681077.

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Inflammatory signaling pathways induced by Helicobacter pylori remain unclear, having been studied mostly on cell-line models derived from gastric adenocarcinoma with potentially altered signaling pathways and nonfunctional receptors. Here, H. pylori-induced signaling pathways were investigated in primary human gastric epithelial cells. Inflammatory response was analyzed on chemokine mRNA expression and production after infection of gastric epithelial cells by H. pylori strains, B128 and B128Δ cagM, a cag type IV secretion system defective strain. Signaling pathway involvement was investigated using inhibitors of epidermal growth factor receptor (EGFR), MAPK, JAK and blocking Abs against TLR2 and TLR4. Inhibitors of EGFR, MAPK and JAK significantly reduced the chemokine mRNA expression and production induced by both H. pylori strains at 3 h and 24 h post-infection. JNK inhibitor reduced chemokine production at 24 h post-infection. Blocking Abs against TLR2 but not TLR4 showed significant reduction of chemokine secretion. Using primary culture of human gastric epithelial cells, our data suggest that H. pylori can be recognized by TLR2, leading to chemokine induction, and that EGFR, MAPK and the JAK/STAT signaling pathways play a key role in the H. pylori-induced CXCL1, CXCL5 and CXCL8 response in a cag pathogenicity island-independent manner.

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Wroblewski, Lydia, Eunyoung Choi, Christine Petersen, Alberto Delgado, M. Blanca Piazuelo, Judith Romero-Gallo, Robert J. Coffey, James R. Goldenring, Annie E. Zemper, and Richard M. Peek. "814 – Helicobacter Pylori Induces Aberrant Lrig1 Stem Cell Activity Within the Stomach in a Cag Type Iv Secretion System-Dependent Manner." Gastroenterology 156, no. 6 (May 2019): S—171—S—172. http://dx.doi.org/10.1016/s0016-5085(19)37220-8.

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Kim, Sung Soo, Dae Young Cheung, and Soo-Heon Park. "Differences of mutation of helicobacter pylori cagA gene isolated from duodenal ulcer and gastric cancer." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 69. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.69.

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69 Background: H. pylori is the pathogen of both duodenal ulcer and gastric carcinoma. However, they are markedly different in terms of its physiologic and pathologic basis. CagA is 120-145-kDa protein of H. pylori and located one end of Cag PAI encoding components of type IV secretion system. H. pylori expressing CagA are associated with development of atrophic gastritis, peptic ulcer, and gastric carcinoma. This study was aimed to examine the differences of cagA mutations of H. pylori isolated from duodenal ulcer and gastric carcinoma. Methods: Isolated H. pylori from 29 patients with gastric carcinoma and 31 patients with duodenal ulcer were compared the frequency of mutations after cloning of cagA of H. pylori. Results: Even there were diverse mutations scattered on whole sequence of cagA, mutations were more frequent in amino acid sequence 200-400 and 850-1100. Amino acid loci G311, D371, M393, T899, and S1068 were mutated in more than half of patients regardless of diseases. The mutations of CagA in C-terminal area, especially Q889, T899, R952, A968, R997, K1034, Q1067, and S1068, were 20% or more frequent in H. pylorifrom duodenal ulcer than those from gastric carcinoma. EPIYA type was not different between the duodenal ulcer and gastric carcinoma. Conclusions: These results suggest that the mutations of cagA of H. pylori, especially in C-terminus are distinguishable between duodenal ulcer and gastric carcinoma.

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Shrestha, Rejina, Naoko Murata-Kamiya, Satoshi Imai, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, and Masanori Hatakeyama. "Mouse Gastric Epithelial Cells Resist CagA Delivery by the Helicobacter pylori Type IV Secretion System." International Journal of Molecular Sciences 23, no. 5 (February 24, 2022): 2492. http://dx.doi.org/10.3390/ijms23052492.

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The initial step in bacterial infection is adherence of the bacterium to the target cell surface. Helicobacter pylori exploits the interaction of bacterial adhesin protein HopQ with human epithelial CEACAMs (CEACAM1, 5, and 6) to stably adhere to gastric epithelial cells, which is necessary for delivery of the H. pylori CagA oncoprotein into the epithelial cells via a type IV secretion system. In contrast to human CEACAMs, however, HopQ does not interact with Ceacam1 (mouse CEACAM1) in vitro or in CHO cells ectopically expressing Ceacam1. Since the mouse genome lacks Ceacam5 and Ceacam6, no significant HopQ–Ceacam interaction may occur in mouse gastric epithelial cells. Here, we found that the mouse stomach has a much lower expression level of Ceacam1 than the expression level of CEACAM1 in the human stomach. Consistently, mouse gastric epithelial cells resist CagA delivery by cagA-positive H. pylori, and the delivery is restored by ectopic expression of human CEACAM1 or CEACAM5 in mouse gastric epithelial cells. Thus, despite the fact that mice are routinely used for H. pylori infection studies, a low expression level of Ceacam1 in the mouse stomach together with the loss or greatly reduced interaction of HopQ with Ceacams make the mouse an inappropriate model for studying the role of H. pylori-delivered CagA in gastric pathogenesis, including the development of gastric cancer.

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Wroblewski, Lydia, Alberto Delgado, Maria B. Piazuelo, Judith Romero-Gallo, Robert J. Coffey, Annie E. Zemper, and Richard M. Peek. "930 HELICOBACTER PYLORI PROMOTES THE DIFFERENTIATION OF PPAR∂-EXPRESSING EPITHELIAL CELLS FROM LRIG+ STEM CELLS IN A CAG TYPE IV SECRETION SYSTEM-DEPENDENT MANNER." Gastroenterology 158, no. 6 (May 2020): S—185. http://dx.doi.org/10.1016/s0016-5085(20)31147-1.

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45

Guiney, Donald G., Patty Hasegawa, and Sheri P. Cole. "Helicobacter pylori Preferentially Induces Interleukin 12 (IL-12) Rather than IL-6 or IL-10 in Human Dendritic Cells." Infection and Immunity 71, no. 7 (July 2003): 4163–66. http://dx.doi.org/10.1128/iai.71.7.4163-4166.2003.

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ABSTRACT Dendritic cells are potent antigen-presenting cells that are present in the gastrointestinal tract and are required for the induction of a Th1 T-cell acquired immune response. Since infection with the gastric pathogen Helicobacter pylori elicits a Th1 cell response, the interaction of these organisms with dendritic cells should reflect the Th1 bias. We incubated H. pylori with cultured human dendritic cells and measured the cytokine induction profile, comparing the response to that induced by Salmonella enterica serovar Typhimurium. We found that H. pylori induced little interleukin 6 (IL-6) and essentially no IL-10 in contrast to S. enterica. However, H. pylori induced levels of IL-12 that were 30% of those induced by S. enterica, indicating a Th1 response. An isogenic cagE mutant of H. pylori lost about 50% of its IL-12-inducing ability, suggesting a role for the cag type IV secretion system in the stimulation of dendritic cells.

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Sharafutdinov, Irshad, Jakob Knorr, Delara Soltan Esmaeili, Steffen Backert, and Nicole Tegtmeyer. "Cortactin Promotes Effective AGS Cell Scattering by Helicobacter pylori CagA, but Not Cellular Vacuolization and Apoptosis Induced by the Vacuolating Cytotoxin VacA." Pathogens 11, no. 1 (December 21, 2021): 3. http://dx.doi.org/10.3390/pathogens11010003.

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Cortactin is an actin-binding protein and actin-nucleation promoting factor regulating cytoskeletal rearrangements in eukaryotes. Helicobacter pylori is a gastric pathogen that exploits cortactin to its own benefit. During infection of gastric epithelial cells, H. pylori hijacks multiple cellular signaling pathways, leading to the disruption of key cell functions. Two bacterial virulence factors play important roles in this scenario, the vacuolating cytotoxin VacA and the translocated effector protein CagA of the cag type IV secretion system (T4SS). Specifically, by overruling the phosphorylation status of cortactin, H. pylori alternates the activity of molecular interaction partners of this important protein, thereby manipulating the performance of cytoskeletal rearrangements, endosomal trafficking and cell movement. Based on shRNA knockdown and other studies, it was previously reported that VacA utilizes cortactin for its cellular uptake, intracellular travel and induction of apoptosis by a mitochondria-dependent mechanism, while CagA induces cell scattering, motility and elongation. To investigate the role of cortactin in these phenotypes in more detail, we produced a complete knockout mutant of cortactin in the gastric adenocarcinoma cell line AGS by CRISPR-Cas9. These cells were infected with H. pylori wild-type or various isogenic mutant strains. Unexpectedly, cortactin deficiency did not prevent the uptake and formation of VacA-dependent vacuoles, nor the induction of apoptosis by internalized VacA, while the induction of T4SS- and CagA-dependent AGS cell movement and elongation were strongly reduced. Thus, we provide evidence that cortactin is required for the function of internalized CagA, but not VacA.

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Hirata, Yoshihiro, Shin Maeda, Yuzo Mituno, Masao Akanuma, Takao Kawabe, Haruhiko Yoshida, Yasushi Shiratori, and Masao Omata. "High prevalence of functional type IV secretion system for CagA protein in Japanese clinical Helicobacter pylori." Gastroenterology 120, no. 5 (April 2001): A652—A653. http://dx.doi.org/10.1016/s0016-5085(08)83244-1.

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48

HIRATA, Y., S. MAEDA, Y. MITUNO, M. AKANUMA, T. KAWABE, H. YOSHIDA, Y. SHIRATORI, and M. OMATA. "High prevalence of functional type IV secretion system for CagA protein in Japanese clinical Helicobacter pylori." Gastroenterology 120, no. 5 (April 2001): A652—A653. http://dx.doi.org/10.1016/s0016-5085(01)83244-3.

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Lai, Chih-Ho, Yun-Chieh Chang, Shin-Yi Du, Hung-Jung Wang, Chun-Hsien Kuo, Shih-Hua Fang, Hua-Wen Fu, Hui-Hao Lin, Ann-Shyn Chiang, and Wen-Ching Wang. "Cholesterol Depletion Reduces Helicobacter pylori CagA Translocation and CagA-Induced Responses in AGS Cells." Infection and Immunity 76, no. 7 (April 28, 2008): 3293–303. http://dx.doi.org/10.1128/iai.00365-08.

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ABSTRACT Infection with Helicobacter pylori cagA-positive strains is associated with gastritis, ulcerations, and gastric cancer. CagA is translocated into infected epithelial cells by a type IV secretion system and can be tyrosine phosphorylated, inducing signal transduction and motogenic responses in epithelial cells. Cellular cholesterol, a vital component of the membrane, contributes to membrane dynamics and functions and is important in VacA intoxication and phagocyte evasion during H. pylori infection. In this investigation, we showed that cholesterol extraction by methyl-β-cyclodextrin reduced the level of CagA translocation and phosphorylation. Confocal microscope visualization revealed that a significant portion of translocated CagA was colocalized with the raft marker GM1 and c-Src during infection. Moreover, GM1 was rapidly recruited into sites of bacterial attachment by live-cell imaging analysis. CagA and VacA were cofractionated with detergent-resistant membranes (DRMs), suggesting that the distribution of CagA and VacA is associated with rafts in infected cells. Upon cholesterol depletion, the distribution shifted to non-DRMs. Accordingly, the CagA-induced hummingbird phenotype and interleukin-8 induction were blocked by cholesterol depletion. Raft-disrupting agents did not influence bacterial adherence but did significantly reduce internalization activity in AGS cells. Together, these results suggest that delivery of CagA into epithelial cells by the bacterial type IV secretion system is mediated in a cholesterol-dependent manner.

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Couturier, Marc Roger, and Markus Stein. "Helicobacter pylori produces unique filaments upon host contact in vitro." Canadian Journal of Microbiology 54, no. 7 (July 2008): 537–48. http://dx.doi.org/10.1139/w08-042.

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Helicobacter pylori exists in 2 distinct morphological states, helicoid and coccoid. Both have been observed in in vitro culture and in gastric biopsies. We visualized H. pylori during AGS cell infections using immunofluorescence microscopy. Anti-H. pylori mouse serum as well as human serum from H. pylori-positive patients recognized long, thin bacterial filaments, which formed on helicoids and more frequently on coccoids. These filaments reached lengths of 59 μm and often connected bacteria. Periodate oxidation abolished antibody recognition, suggesting that carbohydrates compose a major antigenic component of the filaments. Similar to results obtained using immunofluorescence microscopy, scanning electron microscopy imaging revealed thin filamentous structures, which were absent on uninfected cells. Both coccoid conversion and filament development increased over the time course of infection with peak filament formation at 4 h. The number of visible filaments then decreased as bacteria clustered on the apical surface of AGS cells. Since the observed filaments were clearly distinct from previously described surface structures, including flagella and the cag type IV secretion system, our results demonstrate that these filaments represent a unique, previously unrecognized, organelle.

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